61 results on '"Boeckh, Michael"'
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2. BK, JC, and Other Human Polyomaviruses
- Author
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Erard, Veronique, primary and Boeckh, Michael, additional
- Published
- 2012
- Full Text
- View/download PDF
3. Contributors
- Author
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Adderson, Elisabeth E., primary, Agarwal, Aarti, additional, Aldrovandi, Grace M., additional, Allen, Upton D., additional, Amieva, Manuel R., additional, Ampofo, Krow, additional, Anderson, Alicia D., additional, Anderson, Margot, additional, Arguin, Paul M., additional, Arnold, John C., additional, Arvin, Ann M., additional, Ashkenazi, Shai, additional, Baker, Carol J., additional, Barson, William J., additional, Bausch, Daniel G., additional, Bechtel, Kirsten, additional, Benjamin, Daniel K., additional, Berkowitz, Frank E., additional, Blythe, Margaret J., additional, Bocchini, Joseph A., additional, Boeckh, Michael, additional, Bowen, Anna, additional, Bowie, William R., additional, Boyce, Thomas G., additional, Bradley, John S., additional, Brady, Michael T., additional, Bratcher, Denise F., additional, Braverman, Paula K., additional, Hall, Caroline Breese, additional, Bresee, Joseph S., additional, Brook, Itzhak, additional, Bryant, Kristina, additional, Buescher, E. Stephen, additional, Burns, Jane L., additional, Burstein, Gale R., additional, Byington, Carrie L., additional, Byrd, Kathy K., additional, Cappello, Michael, additional, Carter, Bryan D., additional, Cartwright, Emily J., additional, Caserta, Mary T., additional, Cerini, Chiara, additional, Chadwick, Ellen Gould, additional, Cheesebrough, Beth, additional, Chesney, P. Joan, additional, Christenson, John C., additional, Cleary, Thomas G., additional, Coffin, Susan E., additional, Conklin, Laura M., additional, Conklin, Laurie S., additional, Connelly, Beverly L., additional, Contopoulos-Ioannidis, Despina, additional, Conway, James H., additional, Cortese, Margaret M., additional, Cotten, C. Michael, additional, Cox, Elaine, additional, Crockett, Maryanne E., additional, Crowe, James E., additional, Curtis, Nigel, additional, Cunningham, Dennis J., additional, Shortliffe, Linda Marie Dairiki, additional, Darville, Toni, additional, Dasch, Gregory A., additional, Daskalaki, Irini, additional, Daum, Robert S., additional, Dawood, Fatimah S., additional, Demmler, Gail J., additional, Despommier, Dickson D., additional, Diefenbach, Karen A., additional, Dvorak, Christopher C., additional, Edwards, Kathryn M., additional, Edwards, Morven S., additional, Eichenfield, Lawrence F., additional, Elston, Dirk M., additional, Englund, Janet A., additional, Erard, Veronique, additional, Eremeeva, Marina E., additional, Feingold, Anat R., additional, Finn, Adam, additional, Fiore, Anthony E., additional, Fischer, Marc, additional, Fitch, Sarah J., additional, Flynn, Patricia M., additional, Fox, LeAnne M., additional, Frank, Michael M., additional, Fredrick, Douglas R., additional, Friedlander, Sheila Fallon, additional, Gans, Hayley A., additional, Garcia, Carla G., additional, Garzon, Maria C., additional, Gerber, Jeffrey S., additional, Geschwind, Michael D., additional, Gieraltowski, Laura B., additional, Gigliotti, Francis, additional, Gilligan, Peter H., additional, Glaser, Carol, additional, Gold, Benjamin D., additional, Goldstein, Brahm, additional, Gould, Jane M., additional, Green, Michael, additional, Greenberg, David, additional, Griffin, Patricia M., additional, Grom, Alexei A., additional, Gutierrez, Kathleen, additional, Guzman-Cottrill, Judith A., additional, Hall, Aron J., additional, Harper, Marvin B., additional, Harrison, Christopher J., additional, Haslam, David B., additional, Hawkes, Sarah J., additional, Hayes, Edward B., additional, Hazra, Rohan, additional, Heilig, Sara Jane, additional, Hendley, J. Owen, additional, Henry, Marion C.W., additional, Hilinski, Joseph A., additional, Holmberg, Scott D., additional, Holtzman, Deborah, additional, Hotez, Peter J., additional, Hsu, Katherine K., additional, Hu, Dale J., additional, Hwang, Loris Y., additional, Hyun, David Y., additional, Jackson, Mary Anne, additional, Jacobs, Richard F., additional, Jones, Jeffrey L., additional, Kamili, Saleem, additional, Karlowicz, M. Gary, additional, Katz, Ben Z., additional, Kersh, Gilbert J., additional, Kester, Laura M., additional, Keystone, Jay S., additional, Kimberlin, David W., additional, Kleiman, Martin B., additional, Kline, Mark W., additional, Koh, Andrew Y., additional, Konstantopoulos, Andreas, additional, Koranyi, Katalin I., additional, Korgenski, E. Kent, additional, Kroger, Andrew T., additional, Krogstad, Paul, additional, Lauren, Christine T., additional, Lawrence, Hillary S., additional, Leibovitz, Eugene, additional, Levasseur, Stéphanie, additional, Lewis, David B., additional, Lieberman, Jay M., additional, Liu, Jen-Jane, additional, Livingston, Robyn A., additional, Llata, Eloisa, additional, Loharikar, Anagha R., additional, Long, Sarah S., additional, Lopman, Ben A., additional, Lorber, Bennett, additional, Low, Donald E., additional, Lucero, Yalda C., additional, Luján-Zilbermann, Jorge, additional, Luzuriaga, Katherine, additional, MacDonald, Noni E., additional, MacNeil, Adam, additional, Maldonado, Yvonne A., additional, Mani, Chitra S., additional, Marcon, Mario J., additional, Marshall, Gary S., additional, Martin, Stacey W., additional, Matiz, Catalina, additional, Mawle, Alison C., additional, Mazzulli, Tony, additional, McCracken, George H., additional, McDonald, Matthew B., additional, McGregor, Robert S., additional, McIntosh, Kenneth, additional, McMorrow, Meredith, additional, McNeil, Candice, additional, McQuiston, Jennifer H., additional, Meislich, Debrah, additional, Meissner, H. Cody, additional, Mejías, Asunción, additional, Menon, Manoj P., additional, Mertsola, Jussi, additional, Michaels, Marian G., additional, Miller, Melissa B., additional, Mintz, Eric D., additional, Modlin, John F., additional, Mohan, Parvathi, additional, Montgomery, Susan P., additional, Montoya, Jose G., additional, Moore, Zack S., additional, de la Morena, Maite, additional, Moro, Pedro L., additional, Moscicki, Anna-Barbara, additional, Moss, R. Lawrence, additional, Murphy, Trudy V., additional, Murray, Dennis L., additional, Myers, Angela L., additional, Nadel, Simon, additional, Nataro, James P., additional, Neely, Michael N., additional, Nicholson, William L., additional, Nizet, Victor, additional, Nopper, Amy Jo, additional, Norrby-Teglund, Anna, additional, Ochoa, Theresa J., additional, O’Ryan, Miguel, additional, Orenstein, Walter A., additional, Paddock, Christopher D., additional, Pappas, Diane E., additional, Pass, Robert F., additional, Patterson, Thomas F., additional, Pelton, Stephen I., additional, Pickering, Larry K., additional, Piggott, Caroline Diane Sarah, additional, Pizzo, Philip A., additional, Pollard, Andrew J., additional, Posfay-Barbe, Klara M., additional, Poutanen, Susan M., additional, Powell, Dwight A., additional, Prince, Alice S., additional, Prober, Charles G., additional, Ramilo, Octavio, additional, Rangel, Shawn J., additional, Rawstron, Sarah A., additional, Read, Jennifer S., additional, Reed, Michael D., additional, Regan, Joanna J., additional, Reller, Megan E., additional, Reyes, Melissa A., additional, Rice, Peter A., additional, Rice-Townsend, Samuel E., additional, Richards, Frank O., additional, Rodgers, Gail L., additional, Rollin, Pierre E., additional, Romero, José R., additional, Rours, G. Ingrid J.G., additional, Rowley, Anne H., additional, Roy, Sharon L., additional, Rubin, Lorry G., additional, Ruiz-Palacios, Guillermo M., additional, Saiman, Lisa, additional, Sass, Laura, additional, Sauberan, Jason B., additional, Schantz, Peter M., additional, Schneider, Eileen, additional, Schutze, Gordon E., additional, Schwartz, Benjamin, additional, Schwarzwald, Heidi, additional, Shah, Kara N., additional, Shah, Samir S., additional, Shane, Andi L., additional, Shapiro, Craig A., additional, Shapiro, Eugene D., additional, Sharapov, Umid M., additional, Shaw, Jana, additional, Siberry, George Kelly, additional, Siegel, Jane D., additional, Siegel, Robert David, additional, Singh, Nalini, additional, Singh, Upinder, additional, Smith, P. Brian, additional, Snyder, John D., additional, Soper, David E., additional, Staat, Mary Allen, additional, Staples, J. Erin, additional, Starke, Jeffrey R., additional, Steinbach, William J., additional, Stephens, Ina, additional, St. Geme, Joseph W., additional, Stoner, Bradley P., additional, Strober, Jonathan B., additional, Subbarao, Kanta, additional, Sutton, Deanna A., additional, Swanson, Douglas, additional, Takada, Leonel T., additional, Tate, Jacqueline E., additional, Tauxe, Robert V., additional, Tebruegge, Marc, additional, Teshale, Eyasu H., additional, Thompson, George R., additional, Thompson, Herbert A., additional, Thomson, Richard B., additional, Thorell, Emily A., additional, Tohme, Rania A., additional, Tolan, Robert W., additional, Toltzis, Philip, additional, Treat, James, additional, Troy, Stephanie B., additional, Van Dyke, Russell B., additional, Velarde, Jorge J., additional, Vodzak, Jennifer, additional, Wald, Ellen R., additional, Weinberg, Geoffrey A., additional, White, A. Clinton, additional, Widdowson, Marc-Alain, additional, Wiesenfeld, Harold C., additional, Williams, John V., additional, Williams, Roxanne E., additional, Willoughby, Rodney E., additional, Wilson, Craig M., additional, Wingerter, Sarah L., additional, Winkelstein, Jerry A., additional, Workowski, Kimberly A., additional, Wright, Terry W., additional, Yagupsky, Pablo, additional, Yazigi, Nada, additional, Yen, Catherine, additional, Young, Edward J., additional, Zaenglein, Andrea L., additional, and Zaoutis, Theoklis E., additional
- Published
- 2012
- Full Text
- View/download PDF
4. Human Polyomaviruses
- Author
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Erard, Véronique, primary, Limaye, Ajit P., additional, and Boeckh, Michael, additional
- Published
- 2008
- Full Text
- View/download PDF
5. Contributors
- Author
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Adderson, Elisabeth E., primary, Adler-Shohet, Felice C., additional, Amieva, Manuel R., additional, Armstrong, Gregory L., additional, Arvelo, Wences, additional, Arvin, Ann M., additional, Asher, David M., additional, Ashkenazi, Shai, additional, Ault, Kevin A., additional, Baker, Carol J., additional, Barson, William J., additional, Bell, Beth P., additional, Bell, Michael J., additional, Benjamin, Daniel K., additional, Bialek, Stephanie R., additional, Blythe, Margaret J., additional, Bocchini, Joseph A., additional, Boeckh, Michael, additional, Bower, William A., additional, Boyer, Kenneth M., additional, Braden, Christopher R., additional, Bradley, John S., additional, Brady, Michael T., additional, Bratcher, Denise, additional, Braverman, Paula K., additional, Bresee, Joseph S., additional, Brook, Itzhak, additional, Brown, Kevin E., additional, Browning, John C., additional, Buckingham, Steven C., additional, Buescher, E. Stephen, additional, Burns, Jane L., additional, Cappello, Michael, additional, Carter, Bryan D., additional, Chadwick, Ellen Gould, additional, Chesney, Patricia Joan, additional, Childs, James E., additional, Christenson, John C., additional, Cleary, Thomas G., additional, Coffin, Susan E., additional, Connelly, Beverly L., additional, Cotton, C. Michael, additional, Cox, Elaine, additional, Cramer, Robert Andrew, additional, Crockett, Maryanne E., additional, Crowe, James E., additional, Cunningham, Dennis J., additional, Darville, Toni, additional, Dasch, Gregory A., additional, Daum, Robert S., additional, de la Morena, Maite, additional, Demmler, Gail J., additional, Despommier, Dickson D., additional, Diefenbach, Karen A., additional, Dominguez, Elidia, additional, Downs, Stephen M., additional, Dvorak, Christopher C., additional, Edwards, Kathryn, additional, Edwards, Morven S., additional, Englund, Janet A., additional, Erard, Véronique, additional, Eremeeva, Marina E., additional, Finelli, Lyn, additional, Finn, Adam, additional, Fiore, Anthony E., additional, Fischer, Marc, additional, Fitch, Sarah J., additional, Flynn, Patricia M., additional, Fortenberry, J. Dennis, additional, Fox, LeAnne M., additional, Freedman, David O., additional, Gans, Hayley A., additional, Gerber, Michael A., additional, Gigliotti, Francis, additional, Gilligan, Peter, additional, Gold, Benjamin D., additional, Goldman, David L., additional, Goldstein, Brahm, additional, Goldstein, Susan T., additional, Gould, Jane M., additional, Green, Michael, additional, Greene, Sharon K., additional, Greenwald, Mark J., additional, Grom, Alexei A., additional, Grossman, Leigh B., additional, Guerra, Marta A., additional, Gutierrez, Kathleen, additional, Guzman-Cottrill, Judith A., additional, Hall, Caroline Breese, additional, Harper, Marvin B., additional, Haslam, David B., additional, Hayes, Edward B., additional, Hendley, J. Owen, additional, Henrickson, Kelly J., additional, Henry, Marion C.W., additional, Hilinski, Joseph A., additional, Hotez, Peter J., additional, Ingram, David L., additional, Jackson, Mary Anne, additional, Jacobs, Richard F., additional, Karlowicz, M. Gary, additional, Katz, Ben Z., additional, Keystone, Jay S., additional, Kimberlin, David W., additional, Kleiman, Martin B., additional, Klein, Jerome O., additional, Kline, Mark W., additional, Koh, Andrew Y., additional, Koranyi, Katalin I., additional, Korgenski, E. Kent, additional, Leggiadro, Robert J., additional, Levy, Moise L., additional, Lewis, David B., additional, Lieberman, Jay M., additional, Limaye, Abhijit, additional, Lohr, Jacob A., additional, Lorber, Bennett, additional, Long, Sarah S., additional, Low, Donald E., additional, Lowell, Gina, additional, Lowenthal, Elizabeth, additional, Lujan-Zilbermann, Jorge, additional, Luzuriaga, Katherine, additional, MacDonald, Noni E., additional, Maldonado, Yvonne A., additional, Mani, Chitra S., additional, Marcinak, John F., additional, Marcon, Mario J., additional, Marshall, Gary S., additional, Martin, Stacey W., additional, Massung, Robert F., additional, Mast, Eric E., additional, Mazzulli, Tony, additional, McCracken, George H., additional, McGregor, Robert S., additional, McIntosh, Kenneth, additional, McLean, Catherine A., additional, McLeod, Rima, additional, McMillan, Julia A., additional, McQuiston, Jennifer H., additional, Meissner, H. Cody, additional, Menon, Manoj P., additional, Michaels, Marian G., additional, Miller, Melissa B., additional, Millon, Juan Carlos, additional, Modlin, John F., additional, Moore, Matthew R., additional, Moore, Zack S., additional, Moran, Mary M., additional, Moro, Pedro L., additional, Moss, R. Lawrence, additional, Murray, Dennis L., additional, Nadel, Simon, additional, Nataro, James P., additional, Neely, Michael N., additional, Nizet, Victor, additional, Norrby-Teglund, Anna, additional, Nyquist, Ann-Christine, additional, Ochoa, Theresa J., additional, O'Hara, Sara M., additional, Orenstein, Walter A., additional, Ortega-Barria, Eduardo, additional, Overturf, Gary D., additional, Paddock, Christopher D., additional, Painter, John A., additional, Pappas, Diane E., additional, Parise, Monica E., additional, Pass, Robert F., additional, Patterson, Thomas F., additional, Pavia, Andrew T., additional, Pelton, Stephen I., additional, Peter, Georges, additional, Peters, Timothy R., additional, Petri, William A., additional, Pickering, Larry K., additional, Pizzo, Philip A., additional, Pollard, Andrew J., additional, Poutanen, Susan M., additional, Powell, Dwight A., additional, Prince, Alice S., additional, Prober, Charles G., additional, Rangel, Shawn J., additional, Rawstron, Sarah Anne, additional, Reed, Michael D., additional, Reller, Megan E., additional, Richards, Frank O., additional, Rodgers, Gail L., additional, Romero, Luz I., additional, Rotbart, Harley A., additional, Rowley, Anne H., additional, Rubin, Lorry G., additional, Ruiz-Palacios, Guillermo M., additional, Sáez-Llorens, Xavier, additional, Saiman, Lisa, additional, Sauberan, Jason B., additional, Sawyer, Mark H., additional, Schantz, Peter M., additional, Schlager, Theresa A., additional, Schutze, Gordon E., additional, Schwartz, Benjamin, additional, Schwartz, Richard H., additional, Schwarzwald, Heidi, additional, Shah, Samir S., additional, Shane, Andi L., additional, Shapiro, Eugene D., additional, Shetty, Avinash K., additional, Siegel, Jane D., additional, Siegel, Robert D., additional, Sipe, Walter E.B., additional, Skarbinski, Jacek, additional, Smith, P. Brian, additional, Snyder, John D., additional, Solaymani-Mohammadi, Shahram, additional, Staat, Mary Allen, additional, Starke, Jeffrey R., additional, Steinbach, William J., additional, Stephens, Ina, additional, St. Geme, Joseph W., additional, Subbarao, Kanta, additional, Sullivan, John L., additional, Sutton, Deanna A., additional, Sutton, Madeline Y., additional, Swerdlow, David L., additional, Tauxe, Robert V., additional, Thompson, Herbert A., additional, Thomson, Richard B., additional, Thorell, Emily A., additional, Todd, James K., additional, Toltzis, Philip, additional, Tsai, Theodore F., additional, Wald, Ellen R., additional, Wallace, Richard J., additional, Weinberg, Geoffrey A., additional, Weiss, Avery H., additional, White, A. Clinton, additional, Widdowson, Marc-Alain, additional, Williams, Ian T., additional, Williams, John V., additional, Willoughby, Rodney E., additional, Wilson, Craig M., additional, Winkelstein, Jerry A., additional, Workowski, Kimberly, additional, Wright, Terry W., additional, Yazigi, Nada, additional, Yogev, Ram, additional, Young, Edward J., additional, and Zaoutis, Theoklis E., additional
- Published
- 2008
- Full Text
- View/download PDF
6. Human herpesvirus 6 reactivation and disease are infrequent in chimeric antigen receptor T-cell therapy recipients.
- Author
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Kampouri E, Krantz EM, Xie H, Ibrahimi SS, Kiem ES, Sekhon MK, Liang EC, Cowan AJ, Portuguese A, Green DJ, Albittar A, Huang JJ, Gauthier J, Pérez-Osorio AC, Jerome KR, Zerr DM, Boeckh MJ, and Hill JA
- Subjects
- Humans, Male, Female, Middle Aged, Adult, Aged, Prospective Studies, Retrospective Studies, Young Adult, Incidence, Herpesvirus 6, Human immunology, Roseolovirus Infections immunology, Roseolovirus Infections virology, Roseolovirus Infections therapy, Roseolovirus Infections diagnosis, Receptors, Chimeric Antigen immunology, Virus Activation immunology, Immunotherapy, Adoptive methods, Immunotherapy, Adoptive adverse effects
- Abstract
Abstract: Human herpesvirus 6B (HHV-6B) reactivation and disease are increasingly reported after chimeric antigen receptor (CAR) T-cell therapy (CARTx). HHV-6 reactivation in the CAR T-cell product was recently reported, raising questions about product and patient management. Because of overlapping manifestations with immune effector cell-associated neurotoxicity syndrome, diagnosing HHV-6B encephalitis is challenging. We provide 2 lines of evidence assessing the incidence and outcomes of HHV-6B after CARTx. First, in a prospective study with weekly HHV-6B testing for up to 12 weeks after infusion, HHV-6B reactivation occurred in 8 of 89 participants; 3 had chromosomally integrated HHV-6 and were excluded, resulting in a cumulative incidence of HHV-6B reactivation of 6% (95% confidence interval [CI], 2.2-12.5). HHV-6B detection was low level (median peak, 435 copies per mL; interquartile range, 164-979) and did not require therapy. Second, we retrospectively analyzed HHV-6B detection in the blood and/or cerebrospinal fluid (CSF) within 12 weeks after infusion in CARTx recipients. Of 626 patients, 24 had symptom-driven plasma testing, with detection in 1. Among 34 patients with CSF HHV-6 testing, 1 patient had possible HHV-6 encephalitis for a cumulative incidence of 0.17% (95% CI, 0.02-0.94), although symptoms improved without treatment. Our data demonstrate that HHV-6B reactivation and disease are infrequent after CARTx. Routine HHV-6 monitoring is not warranted., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)
- Published
- 2024
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7. Human herpesvirus-6 reactivation and disease after allogeneic haematopoietic cell transplantation in the era of letermovir for cytomegalovirus prophylaxis.
- Author
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Kampouri E, Zamora D, Kiem ES, Liu W, Ibrahimi S, Blazevic RL, Lovas EA, Kimball LE, Huang ML, Jerome KR, Ueda Oshima M, Mielcarek M, Zerr DM, Boeckh MJ, Krantz EM, and Hill JA
- Subjects
- Humans, Retrospective Studies, Male, Middle Aged, Female, Adult, Cytomegalovirus drug effects, Roseolovirus Infections virology, Roseolovirus Infections epidemiology, Roseolovirus Infections prevention & control, Aged, Virus Activation drug effects, Young Adult, Transplantation, Homologous adverse effects, Incidence, Hematopoietic Stem Cell Transplantation adverse effects, Cytomegalovirus Infections prevention & control, Cytomegalovirus Infections epidemiology, Cytomegalovirus Infections virology, Antiviral Agents therapeutic use, Herpesvirus 6, Human drug effects, Quinazolines therapeutic use, Acetates therapeutic use
- Abstract
Objectives: Letermovir for cytomegalovirus (CMV) prophylaxis in allogeneic haematopoietic cell transplant (HCT) recipients has decreased anti-CMV therapy use. Contrary to letermovir, anti-CMV antivirals are also active against human herpesvirus-6 (HHV-6). We assessed changes in HHV-6 epidemiology in the post-letermovir era., Methods: We conducted a retrospective cohort study of CMV-seropositive allogeneic HCT recipients comparing time periods before and after routine use of prophylactic letermovir. HHV-6 testing was at the discretion of clinicians. We computed the cumulative incidence of broad-spectrum antiviral initiation (foscarnet, (val)ganciclovir, and/or cidofovir), HHV-6 testing, and HHV-6 detection in blood and cerebrospinal fluid within 100 days after HCT. We used Cox proportional-hazards models with stabilized inverse probability of treatment weights to compare outcomes between cohorts balanced for baseline factors., Results: We analysed 738 patients, 376 in the pre-letermovir and 362 in the post-letermovir cohort. Broad-spectrum antiviral initiation incidence decreased from 65% (95% CI, 60-70%) pre-letermovir to 21% (95% CI, 17-25%) post-letermovir. The cumulative incidence of HHV-6 testing (17% [95% CI, 13-21%] pre-letermovir versus 13% [95% CI, 10-16%] post-letermovir), detection (3% [95% CI, 1-5%] in both cohorts), and HHV-6 encephalitis (0.5% [95% CI, 0.1-1.8%] pre-letermovir and 0.6% [95% CI, 0.1-1.9%] post-letermovir) were similar between cohorts. First HHV-6 detection occurred at a median of 37 days (interquartile range, 18-58) in the pre-letermovir cohort and 27 (interquartile range, 25-34) in the post-letermovir cohort. In a weighted model, there was no association between the pre-versus post-letermovir cohort and HHV-6 detection (adjusted hazard ratio, 1.08; 95% CI, 0.44-2.62)., Discussion: Despite a large decrease in broad-spectrum antivirals after the introduction of letermovir prophylaxis in CMV-seropositive allogeneic HCT recipients, there was no evidence for increased clinically detected HHV-6 reactivation and disease., (Copyright © 2023 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)
- Published
- 2023
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8. How I prevent viral reactivation in high-risk patients.
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Dadwal SS, Papanicolaou GA, and Boeckh M
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- Humans, Herpesvirus 4, Human, Antiviral Agents therapeutic use, Hematopoietic Stem Cell Transplantation adverse effects, Epstein-Barr Virus Infections complications, Epstein-Barr Virus Infections prevention & control, Virus Diseases prevention & control, Virus Diseases etiology
- Abstract
Preventing viral infections at an early stage is a key strategy for successfully improving transplant outcomes. Preemptive therapy and prophylaxis with antiviral agents have been successfully used to prevent clinically significant viral infections in hematopoietic cell transplant recipients. Major progress has been made over the past decades in preventing viral infections through a better understanding of the biology and risk factors, as well as the introduction of novel antiviral agents and advances in immunotherapy. High-quality evidence exists for the effective prevention of herpes simplex virus, varicella-zoster virus, and cytomegalovirus infection and disease. Few data are available on the effective prevention of human herpesvirus 6, Epstein-Barr virus, adenovirus, and BK virus infections. To highlight the spectrum of clinical practice, here we review high-risk situations that we handle with a high degree of uniformity and cases that feature differences in approaches, reflecting distinct hematopoietic cell transplant practices, such as ex vivo T-cell depletion., (© 2023 by The American Society of Hematology.)
- Published
- 2023
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9. Genetic variants associated with cytomegalovirus infection after allogeneic hematopoietic cell transplantation.
- Author
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Casto AM, Seo S, Levine DM, Storer BE, Dong X, Hansen JA, Boeckh M, and Martin PJ
- Subjects
- ATP Binding Cassette Transporter, Subfamily B genetics, Adolescent, Adult, Aged, Child, Child, Preschool, Cytomegalovirus isolation & purification, Cytomegalovirus physiology, Cytomegalovirus Infections etiology, Female, GTP-Binding Protein Regulators genetics, Genome-Wide Association Study, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Transplantation, Homologous adverse effects, Virus Activation, Young Adult, Cytomegalovirus Infections genetics, Hematopoietic Stem Cell Transplantation adverse effects
- Abstract
Human cytomegalovirus (CMV) reactivation is a frequent complication of allogeneic hematopoietic cell transplantation (HCT). Despite routine screening for CMV reactivation and early antiviral treatment, the rates of CMV-related complications after HCT remain high. Genetic variants in both the donor and recipient have been associated with the risk of CMV reactivation and disease after HCT, but these associations have not been validated, and their clinical importance remains unclear. In this study, we assessed 117 candidate variants previously associated with CMV-related phenotypes for association with CMV reactivation and disease in a cohort of 2169 CMV-seropositive HCT recipients. We also carried out a genome-wide association study (GWAS) for CMV reactivation and disease in the same cohort. Both analyses used a prespecified discovery and replication approach to control the risk of false-positive results. Among the 117 candidate variants, our analysis implicates only the donor ABCB1 rs1045642 genotype as a risk factor for CMV reactivation. This synonymous variant in P-glycoprotein may influence the risk of CMV reactivation by altering the efflux of cyclosporine and tacrolimus from donor lymphocytes. In the GWAS analysis, the donor CDC42EP3 rs11686168 genotype approached the significance threshold for association with CMV reactivation, although we could not identify a mechanism to explain this association. The results of this study suggest that most genomic variants previously associated with CMV phenotypes do not significantly alter the risk for CMV reactivation or disease after HCT., (© 2021 by The American Society of Hematology.)
- Published
- 2021
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10. Cytomegalovirus-specific T-cell reconstitution following letermovir prophylaxis after hematopoietic cell transplantation.
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Zamora D, Duke ER, Xie H, Edmison BC, Akoto B, Kiener R, Stevens-Ayers T, Wagner R, Mielcarek M, Leisenring WM, Jerome KR, Schiffer JT, Finak G, De Rosa SC, and Boeckh M
- Subjects
- Adult, Aged, Cytomegalovirus drug effects, Cytomegalovirus Infections immunology, Cytomegalovirus Infections virology, Disease-Free Survival, Female, Humans, Linear Models, Lymphocyte Count, Male, Middle Aged, Multivariate Analysis, Phenotype, T-Lymphocytes drug effects, Virus Activation drug effects, Young Adult, Acetates pharmacology, Cytomegalovirus immunology, Hematopoietic Stem Cell Transplantation, Quinazolines pharmacology, T-Lymphocytes immunology
- Abstract
Decreased cytomegalovirus (CMV)-specific immunity after hematopoietic cell transplantation (HCT) is associated with late CMV reactivation and increased mortality. Whether letermovir prophylaxis-associated reduction in viral exposure influences CMV-specific immune reconstitution is unknown. In a prospective cohort of allogeneic HCT recipients who received letermovir, we compared polyfunctional CMV-specific T-cell responses to those of controls who received PCR-guided preemptive therapy before the introduction of letermovir. Thirteen-color flow cytometry was used to assess T-cell responses at 3 months after HCT following stimulation with CMV immediate early-1 (IE-1) antigen and phosphoprotein 65 (pp65) antigens. Polyfunctionality was characterized by combinatorial polyfunctionality analysis of antigen-specific T-cell subsets. Use of letermovir and reduction of viral exposure were assessed for their association with CMV-specific T-cell immunity. Polyfunctional T-cell responses to IE-1 and pp65 were decreased in letermovir recipients and remained diminished after adjustment for donor CMV serostatus, absolute lymphocyte count, and steroid use. Among letermovir recipients, greater peak CMV DNAemia and increased viral shedding were associated with stronger CD8+ responses to pp65, whereas the CMV shedding rate was associated with greater CD4+ responses to IE-1. In summary, our study provided initial evidence that letermovir may delay CMV-specific cellular reconstitution, possibly related to decreased CMV antigen exposure. Evaluating T-cell polyfunctionality may identify patients at risk for late CMV infection after HCT., (© 2021 by The American Society of Hematology.)
- Published
- 2021
- Full Text
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11. Multicenter evaluation of parametric response mapping as an indicator of bronchiolitis obliterans syndrome after hematopoietic stem cell transplantation.
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Cheng GS, Selwa KE, Hatt C, Ram S, Fortuna AB, Guerriero M, Himelhoch B, McAree D, Hoffman TC, Brisson J, Nazareno R, Bloye K, Johnson TD, Remberger M, Mattsson J, Vummidi D, Kazerooni EE, Lama VN, Galban S, Boeckh M, Yanik GA, and Galban CJ
- Subjects
- Forced Expiratory Volume, Humans, Lung, Retrospective Studies, Bronchiolitis Obliterans diagnostic imaging, Bronchiolitis Obliterans etiology, Hematopoietic Stem Cell Transplantation adverse effects, Lung Transplantation
- Abstract
Parametric response mapping (PRM) is a novel computed tomography (CT) technology that has shown potential for assessment of bronchiolitis obliterans syndrome (BOS) after hematopoietic stem cell transplantation (HCT). The primary aim of this study was to evaluate whether variations in image acquisition under real-world conditions affect the PRM measurements of clinically diagnosed BOS. CT scans were obtained retrospectively from 72 HCT recipients with BOS and graft-versus-host disease from Fred Hutchinson Cancer Research Center, Karolinska Institute, and the University of Michigan. Whole lung volumetric scans were performed at inspiration and expiration using site-specific acquisition and reconstruction protocols. PRM and pulmonary function measurements were assessed. Patients with moderately severe BOS at diagnosis (median forced expiratory volume at 1 second [FEV1] 53.5% predicted) had similar characteristics between sites. Variations in site-specific CT acquisition protocols had a negligible effect on the PRM-derived small airways disease (SAD), that is, BOS measurements. PRM-derived SAD was found to correlate with FEV1% predicted and FEV1/ forced vital capacity (R = -0.236, P = .046; and R = -0.689, P < .0001, respectively), which suggests that elevated levels in the PRM measurements are primarily affected by BOS airflow obstruction and not CT scan acquisition parameters. Based on these results, PRM may be applied broadly for post-HCT diagnosis and monitoring of BOS., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)
- Published
- 2020
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12. How I treat CMV reactivation after allogeneic hematopoietic stem cell transplantation.
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Einsele H, Ljungman P, and Boeckh M
- Subjects
- Adult, Cytomegalovirus isolation & purification, Cytomegalovirus Infections etiology, Cytomegalovirus Infections pathology, Female, Humans, Male, Middle Aged, Prognosis, Viral Load, Antiviral Agents therapeutic use, Cytomegalovirus drug effects, Cytomegalovirus Infections drug therapy, Hematologic Diseases therapy, Hematopoietic Stem Cell Transplantation adverse effects, Virus Activation drug effects
- Abstract
Cytomegalovirus (CMV) reactivation remains one of the most common and life-threatening infectious complications following allogeneic hematopoietic stem cell transplantation, despite novel diagnostic technologies, several novel prophylactic agents, and further improvements in preemptive therapy and treatment of established CMV disease. Treatment decisions for CMV reactivation are becoming increasingly difficult and must take into account whether the patient has received antiviral prophylaxis, the patient's individual risk profile for CMV disease, CMV-specific T-cell reconstitution, CMV viral load, and the potential drug resistance detected at the time of initiation of antiviral therapy. Thus, we increasingly use personalized treatment strategies for the recipient of an allograft with CMV reactivation based on prior use of anti-CMV prophylaxis, viral load, the assessment of CMV-specific T-cell immunity, and the molecular assessment of resistance to antiviral drugs., (© 2020 by The American Society of Hematology.)
- Published
- 2020
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13. Oral brincidofovir decreases the incidence of HHV-6B viremia after allogeneic HCT.
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Hill JA, Nichols WG, Marty FM, Papanicolaou GA, Brundage TM, Lanier R, Zerr DM, and Boeckh MJ
- Subjects
- Administration, Oral, Adolescent, Adult, Aged, Antiviral Agents administration & dosage, Cohort Studies, Cytosine administration & dosage, DNA, Viral, Female, Follow-Up Studies, Graft vs Host Disease epidemiology, Graft vs Host Disease etiology, Hematologic Neoplasms pathology, Humans, Incidence, Male, Middle Aged, Prognosis, Randomized Controlled Trials as Topic, Roseolovirus Infections epidemiology, Roseolovirus Infections etiology, United States epidemiology, Viral Load, Viremia epidemiology, Viremia etiology, Virus Activation, Young Adult, Cytosine analogs & derivatives, Graft vs Host Disease drug therapy, Hematologic Neoplasms therapy, Hematopoietic Stem Cell Transplantation adverse effects, Herpesvirus 6, Human isolation & purification, Organophosphonates administration & dosage, Roseolovirus Infections drug therapy, Viremia drug therapy
- Abstract
Human herpesvirus 6B (HHV-6B) frequently reactivates after allogeneic hematopoietic cell transplantation (HCT). There are no randomized studies of antiviral treatments to prevent HHV-6B reactivation. Brincidofovir has high in vitro activity against HHV-6B and other DNA viruses, but its in vivo activity for HHV-6B has not been demonstrated. We performed a post hoc analysis of a randomized controlled trial of twice-weekly oral brincidofovir for cytomegalovirus prophylaxis after allogeneic HCT to study the effect of brincidofovir on HHV-6B reactivation. We included patients randomized within 2 weeks of HCT and who received at least 6 consecutive doses of study drug after randomization. We tested plasma for HHV-6B through week 6 post-HCT. The cohort consisted of 92 patients receiving brincidofovir and 61 receiving placebo. The cumulative incidence of HHV-6B plasma detection through day 42 post-HCT was significantly lower among patients receiving brincidofovir (14.2%) compared with placebo (32.4%; log-rank, 0.019). In an adjusted Cox model, brincidofovir exposure remained associated with a lower hazard for HHV-6B plasma detection (hazard ratio, 0.40; 95% confidence interval, 0.20-0.80). In conclusion, brincidofovir prophylaxis reduced HHV-6B reactivation after allogeneic HCT in a post hoc analysis of a randomized controlled trial. These data support the study of intravenous brincidofovir for HHV-6B prophylaxis., (© 2020 by The American Society of Hematology.)
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- 2020
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14. Comprehensive viromewide antibody responses by systematic epitope scanning after hematopoietic cell transplantation.
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Bender Ignacio RA, Dasgupta S, Stevens-Ayers T, Kula T, Hill JA, Lee SJ, Mielcarek M, Duerr A, Elledge SJ, and Boeckh M
- Subjects
- Adult, Antibodies, Viral blood, Antibody Formation genetics, Cytomegalovirus immunology, Female, Follow-Up Studies, Graft vs Host Disease etiology, HLA Antigens genetics, HLA Antigens immunology, Humans, Male, Middle Aged, Postoperative Period, Tissue Donors, Transplant Recipients, Transplantation, Homologous, Antibodies, Viral immunology, Antibody Formation immunology, Epitopes immunology, Hematopoietic Stem Cell Transplantation adverse effects, Immunity, Humoral
- Abstract
Further insight into humoral viral immunity after hematopoietic cell transplantation (HCT) could have potential impact on donor selection or monitoring of patients. Currently, estimation of humoral immune recovery is inferred from lymphocyte counts or immunoglobulin levels and does not address vulnerability to specific viral infections. We interrogated the viral antibody repertoire before and after HCT using a novel serosurvey (VirScan) that detects immunoglobulin G responses to 206 viruses. We performed VirScan on cryopreserved serum from pre-HCT and 30, 100, and 365 days after myeloablative HCT from 37 donor-recipient pairs. We applied ecologic metrics (α- and β-diversity) and evaluated predictors of metrics and changes over time. Donor age and donor/recipient cytomegalovirus (CMV) serostatus and receipt systemic glucocorticoids were most strongly associated with VirScan metrics at day 100. Other clinical characteristics, including pre-HCT treatment and conditioning, did not affect antiviral repertoire metrics. The recipient repertoire was most similar (pairwise β-diversity) to that of donor at day 100, but more similar to pre-HCT self by day 365. Gain or loss of epitopes to common viruses over the year post-HCT differed by donor and recipient pre-HCT serostatus, with highest gains in naive donors to seropositive recipients for several human herpesviruses and adenoviruses. We used VirScan to highlight contributions of donor and recipient to antiviral humoral immunity and evaluate longitudinal changes. This work builds a foundation to test whether such systematic profiling could serve as a biomarker of immune reconstitution, predict clinical events after HCT, or help refine selection of optimal donors., (© 2019 by The American Society of Hematology.)
- Published
- 2019
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15. Inactivated varicella zoster vaccine in autologous haemopoietic stem-cell transplant recipients: an international, multicentre, randomised, double-blind, placebo-controlled trial.
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Winston DJ, Mullane KM, Cornely OA, Boeckh MJ, Brown JW, Pergam SA, Trociukas I, Žák P, Craig MD, Papanicolaou GA, Velez JD, Panse J, Hurtado K, Fernsler DA, Stek JE, Pang L, Su SC, Zhao Y, Chan ISF, Kaplan SS, Parrino J, Lee I, Popmihajlov Z, Annunziato PW, and Arvin A
- Subjects
- Adult, Aged, Double-Blind Method, Female, Humans, Leukemia therapy, Lymphoma therapy, Male, Middle Aged, Multiple Myeloma therapy, Transplantation, Autologous, Vaccines, Inactivated, Young Adult, Hematopoietic Stem Cell Transplantation, Herpes Zoster prevention & control, Herpes Zoster Vaccine
- Abstract
Background: Recipients of autologous haemopoietic stem-cell transplants (auto-HSCT) have an increased risk of herpes zoster and herpes zoster-related complications. The aim of this study was to establish the efficacy and safety of an inactivated varicella zoster vaccine for the prevention of herpes zoster after auto-HSCT., Methods: In this randomised, double-blind, placebo-controlled phase 3 trial, participants were recruited from 135 medical centres (ie, stem-cell transplant centres and hospitals) in North America, South America, Europe, and Asia. Patients were eligible if they were aged 18 years or older, scheduled to receive an auto-HSCT within 60 days of enrolment, and had a history of varicella infection or were seropositive for antibodies to varicella zoster virus, or both. Exclusion criteria included a history of herpes zoster within the previous year of enrolment, and intended antiviral prophylaxis for longer than 6 months after transplantation. Participants were randomly assigned according to a central randomisation schedule generated by the trial statistician, to receive either the inactivated-virus vaccine from one of three consistency lots, a high-antigen lot, or placebo, stratified by age (<50 vs ≥50 years) and intended duration of antiviral prophylaxis after transplantation (≤3 months vs >3 to ≤6 months). Participants, investigators, trial staff, and the funder's clinical and laboratory personnel were masked to group assignment. Participants were given four doses of inactivated vaccine or placebo, with the first dose 5-60 days before auto-HSCT, and the second, third, and fourth doses at about 30, 60, and 90 days after transplantation. The primary efficacy endpoint was the incidence of herpes zoster, confirmed by PCR or adjudication by a masked clinical committee, or both, assessed in all participants randomly assigned to the vaccine consistency lot group or placebo group who received at least one dose of vaccine and had auto-HSCT. Safety was assessed in all randomised participants who received at least one dose of vaccine and had follow-up data. A prespecified vaccine efficacy success criterion required the lower bound of the 95% CI be higher than 25% for the relative reduction of the hazard ratio of herpes zoster infection in participants given the vaccine from one of the consistency lots compared with those given placebo. This trial is registered on ClinicalTrials.gov (NCT01229267) and EudraCT (2010-020150-34)., Findings: Between Dec 7, 2010, and April 25, 2013, 560 participants were randomly assigned to the vaccine consistency lot group, 106 to the high-antigen lot group, and 564 to the placebo group. 249 (44%) of patients in the vaccine consistency lot group, 35 (33%) in the high-antigen lot group, and 220 (39%) in the placebo group discontinued before study end, mostly because of death or withdrawal. 51 participants were excluded from the primary efficacy endpoint analyses because they did not undergo auto-HSCT or were not vaccinated, or both (22 [4%] in the vaccine consistency lot group, and 29 [5%] in the placebo group). Mean follow-up for efficacy was 2·4 years (SD 1·3) in the vaccine consistency lot group and 2·3 years (SD 1·3) in the placebo group. 42 (8%) of 538 participants in the vaccine consistency lot group (32·9 per 1000 person-years) and 113 (21%) of 535 in the placebo group (91·9 per 1000 person-years) had a confirmed case of herpes zoster. The estimated vaccine efficacy was 63·8% (95% CI 48·4-74·6), meeting the pre-specified success criterion. For the combined vaccine groups versus the placebo group, the proportion of patients with serious adverse events (216 [33%] of 657 vs 181 [33%] of 554; risk difference 0·2%, 95% CI -5·1 to 5·5) and serious vaccine-related adverse events (five [1%] vs five [1%]; risk difference 0·1%, -1·4 to 1·1) were similar. Vaccine-related injection-site adverse events occurred more frequently in participants given vaccine than those given placebo (191 [29%] vs 36 [7%]; risk difference 22·6%, 95% CI 18·5-26·6; p<0·0001)., Interpretation: This study shows for the first time in a large phase 3 trial that early vaccination of auto-HSCT recipients during the peri-transplant period can be effective for the prevention of an opportunistic infection like herpes zoster and that the vaccine is well tolerated., Funding: Merck & Co., Inc., (Copyright © 2018 Elsevier Ltd. All rights reserved.)
- Published
- 2018
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16. Infectious complications of CD19-targeted chimeric antigen receptor-modified T-cell immunotherapy.
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Hill JA, Li D, Hay KA, Green ML, Cherian S, Chen X, Riddell SR, Maloney DG, Boeckh M, and Turtle CJ
- Subjects
- Adult, Aged, Cell- and Tissue-Based Therapy adverse effects, Cohort Studies, Female, Follow-Up Studies, Humans, Infections etiology, Leukemia, Lymphocytic, Chronic, B-Cell immunology, Lymphoma, Non-Hodgkin immunology, Male, Middle Aged, Precursor Cell Lymphoblastic Leukemia-Lymphoma immunology, Prognosis, Severity of Illness Index, T-Lymphocytes immunology, United States epidemiology, Young Adult, Immunotherapy adverse effects, Infections epidemiology, Leukemia, Lymphocytic, Chronic, B-Cell therapy, Lymphoma, Non-Hodgkin therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma therapy, Receptors, Antigen, T-Cell metabolism, T-Lymphocytes transplantation
- Abstract
Lymphodepletion chemotherapy with CD19-targeted chimeric antigen receptor-modified T (CAR-T)-cell immunotherapy is a novel treatment for refractory or relapsed B-cell malignancies. Infectious complications of this approach have not been systematically studied. We evaluated infections occurring between days 0 to 90 in 133 patients treated with CD19 CAR-T cells in a phase 1/2 study. We used Poisson and Cox regression to evaluate pre- and posttreatment risk factors for infection, respectively. The cohort included patients with acute lymphoblastic leukemia (ALL; n = 47), chronic lymphocytic leukemia (n = 24), and non-Hodgkin lymphoma (n = 62). There were 43 infections in 30 of 133 patients (23%) within 28 days after CAR-T-cell infusion with an infection density of 1.19 infections for every 100 days at risk. There was a lower infection density of 0.67 between days 29 and 90 ( P = .02). The first infection occurred a median of 6 days after CAR-T-cell infusion. Six patients (5%) developed invasive fungal infections and 5 patients (4%) had life-threatening or fatal infections. Patients with ALL, ≥4 prior antitumor regimens, and receipt of the highest CAR-T-cell dose (2 × 10
7 cells per kg) had a higher infection density within 28 days in an adjusted model of baseline characteristics. Cytokine release syndrome (CRS) severity was the only factor after CAR-T-cell infusion associated with infection in a multivariable analysis. The incidence of infections was comparable to observations from clinical trials of salvage chemoimmunotherapies in similar patients. This trial was registered at www.clinicaltrials.gov as #NCT01865617., (© 2018 by The American Society of Hematology.)- Published
- 2018
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17. Outcomes of hematopoietic cell transplantation using donors or recipients with inherited chromosomally integrated HHV-6.
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Hill JA, Magaret AS, Hall-Sedlak R, Mikhaylova A, Huang ML, Sandmaier BM, Hansen JA, Jerome KR, Zerr DM, and Boeckh M
- Subjects
- Acute Disease, Adult, Chronic Disease, Female, Graft vs Host Disease genetics, Humans, Incidence, Kaplan-Meier Estimate, Male, Middle Aged, Multivariate Analysis, Probability, Proportional Hazards Models, Risk Factors, Treatment Outcome, Chromosomes, Human genetics, Chromosomes, Human virology, Hematopoietic Stem Cell Transplantation, Herpesvirus 6, Human genetics, Inheritance Patterns genetics, Tissue Donors
- Abstract
Human herpesvirus 6 (HHV-6) species have a unique ability to integrate into chromosomal telomeres. Mendelian inheritance via gametocyte integration results in HHV-6 in every nucleated cell. The epidemiology and clinical effect of inherited chromosomally integrated HHV-6 (iciHHV-6) in hematopoietic cell transplant (HCT) recipients is unclear. We identified 4319 HCT donor-recipient pairs (8638 subjects) who received an allogeneic HCT and had archived pre-HCT peripheral blood mononuclear cell samples. We screened these samples for iciHHV-6 and compared characteristics of HCT recipients and donors with iciHHV-6 with those of recipients and donors without iciHHV-6, respectively. We calculated Kaplan-Meier probability estimates and Cox proportional hazards models for post-HCT outcomes based on recipient and donor iciHHV-6 status. We identified 60 HCT recipients (1.4%) and 40 donors (0.9%) with iciHHV-6; both recipient and donor harbored iciHHV-6 in 13 HCTs. Thus, there were 87 HCTs (2%) in which the recipient, donor, or both harbored iciHHV-6. Acute graft-versus-host disease (GVHD) grades 2-4 was more frequent when recipients or donors had iciHHV-6 (adjusted hazard ratios, 1.7-1.9; P = .004-.001). Cytomegalovirus viremia (any and high-level) was more frequent among recipients with iciHHV-6 (adjusted HRs, 1.7-3.1; P = .001-.040). Inherited ciHHV-6 status did not significantly affect risk for chronic GVHD, hematopoietic cell engraftment, overall mortality, or nonrelapse mortality. Screening for iciHHV-6 could guide donor selection and post-HCT risk stratification and treatment. Further study is needed to replicate these findings and identify potential mechanisms., (© 2017 by The American Society of Hematology.)
- Published
- 2017
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18. Validation of single nucleotide polymorphisms in invasive aspergillosis following hematopoietic cell transplantation.
- Author
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Fisher CE, Hohl TM, Fan W, Storer BE, Levine DM, Zhao LP, Martin PJ, Warren EH, Boeckh M, and Hansen JA
- Subjects
- Adult, C-Reactive Protein genetics, Cohort Studies, Female, Genetic Predisposition to Disease, Genotype, Humans, Lectins, C-Type genetics, Male, Middle Aged, Serum Amyloid P-Component genetics, Aspergillosis etiology, Aspergillosis genetics, Hematopoietic Stem Cell Transplantation adverse effects, Polymorphism, Single Nucleotide
- Abstract
Invasive aspergillosis (IA) is a significant cause of morbidity and mortality following allogeneic hematopoietic cell transplantation (HCT). Previous studies have reported an association between IA development and single nucleotide polymorphisms (SNPs), but many SNPs have not been replicated in a separate cohort. The presence of a positive serum galactomannan assay (SGM+) has also been associated with a worse prognosis in patients with IA, and genetic determinants in this subset of patients have not been systematically studied. The study cohort included 2609 HCT recipients and their donor pairs: 483 with proven/probable IA (183 SGM+) and 2126 with no IA by standard criteria. Of 25 SNPs previously published, we analyzed 20 in 14 genes that passed quality control. Samples were genotyped via microarray, and SNPs that could not be genotyped were imputed. The primary aim was to replicate SNPs associated with proven/probable IA at 2 years; secondary goals were to explore the associations using an end point of SGM+ IA or proven/probable IA using a different genetic model or time to IA (3 months vs 2 years) compared with the original study. Two SNPs in 2 genes ( PTX3 , CLEC7a ) were replicated. Thirteen SNPs in 9 genes had an association at P ≤ .05 using the secondary aims ( PTX3 , CLEC7a , CD209 , CXCL10 , TLR6 , S100B , IFNG , PLG , TNFR1 ), with hazard ratios ranging from 1.2 to 3.29. Underlying genetic differences can influence development of IA following HCT. Identification of genetic predispositions to IA could have important implications in donor screening, risk stratification of recipients, monitoring, and prophylaxis., (© 2017 by The American Society of Hematology.)
- Published
- 2017
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19. The cumulative burden of double-stranded DNA virus detection after allogeneic HCT is associated with increased mortality.
- Author
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Hill JA, Mayer BT, Xie H, Leisenring WM, Huang ML, Stevens-Ayers T, Milano F, Delaney C, Sorror ML, Sandmaier BM, Nichols G, Zerr DM, Jerome KR, Schiffer JT, and Boeckh M
- Subjects
- Adenoviridae genetics, Adenoviridae isolation & purification, Adenoviridae Infections diagnosis, Adenoviridae Infections immunology, Adenoviridae Infections virology, Adult, Area Under Curve, BK Virus genetics, BK Virus isolation & purification, Child, Cord Blood Stem Cell Transplantation mortality, Cytomegalovirus genetics, Cytomegalovirus isolation & purification, DNA, Viral genetics, Female, Graft vs Host Disease immunology, Graft vs Host Disease mortality, Graft vs Host Disease pathology, Herpesviridae Infections diagnosis, Herpesviridae Infections immunology, Herpesviridae Infections virology, Herpesvirus 4, Human genetics, Herpesvirus 4, Human isolation & purification, Herpesvirus 6, Human genetics, Herpesvirus 6, Human isolation & purification, Humans, Male, Middle Aged, Opportunistic Infections diagnosis, Opportunistic Infections immunology, Opportunistic Infections virology, Proportional Hazards Models, Real-Time Polymerase Chain Reaction, Retrospective Studies, Risk Factors, Transplantation, Homologous, Unrelated Donors, Viral Load, Adenoviridae Infections mortality, DNA, Viral isolation & purification, Hematopoietic Stem Cell Transplantation mortality, Herpesviridae Infections mortality, Opportunistic Infections mortality
- Abstract
Strategies to prevent active infection with certain double-stranded DNA (dsDNA) viruses after allogeneic hematopoietic cell transplantation (HCT) are limited by incomplete understanding of their epidemiology and clinical impact. We retrospectively tested weekly plasma samples from allogeneic HCT recipients at our center from 2007 to 2014. We used quantitative PCR to test for cytomegalovirus, BK polyomavirus, human herpesvirus 6B, HHV-6A, adenovirus, and Epstein-Barr virus between days 0 and 100 post-HCT. We evaluated risk factors for detection of multiple viruses and association of viruses with mortality through day 365 post-HCT with Cox models. Among 404 allogeneic HCT recipients, including 125 cord blood, 125 HLA-mismatched, and 154 HLA-matched HCTs, detection of multiple viruses was common through day 100: 90% had ≥1, 62% had ≥2, 28% had ≥3, and 5% had 4 or 5 viruses. Risk factors for detection of multiple viruses included cord blood or HLA-mismatched HCT, myeloablative conditioning, and acute graft-versus-host disease ( P values < .01). Absolute lymphocyte count of <200 cells/mm
3 was associated with greater virus exposure on the basis of the maximum cumulative viral load area under the curve (AUC) ( P = .054). The maximum cumulative viral load AUC was the best predictor of early (days 0-100) and late (days 101-365) overall mortality (adjusted hazard ratio [aHR] = 1.36, 95% confidence interval [CI] [1.25, 1.49], and aHR = 1.04, 95% CI [1.0, 1.08], respectively) after accounting for immune reconstitution and graft-versus-host disease. In conclusion, detection of multiple dsDNA viruses was frequent after allogeneic HCT and had a dose-dependent association with increased mortality. These data suggest opportunities to improve outcomes with better antiviral strategies., (© 2017 by The American Society of Hematology.)- Published
- 2017
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20. Replication of associations between genetic polymorphisms and chronic graft-versus-host disease.
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Martin PJ, Fan W, Storer BE, Levine DM, Zhao LP, Warren EH, Flowers ME, Lee SJ, Carpenter PA, Boeckh M, Hingorani S, Yan L, Hu Q, Preus L, Liu S, Spellman S, Zhu X, Pasquini M, McCarthy P, Stram D, Sheng X, Pooler L, Haiman CA, Sucheston-Campbell L, Hahn T, and Hansen JA
- Subjects
- Adolescent, Adult, Aged, Child, Child, Preschool, Chronic Disease, Cohort Studies, Female, Genetic Association Studies, Hematopoietic Stem Cell Transplantation, Histocompatibility Testing, Humans, Infant, Infant, Newborn, Male, Middle Aged, Transplantation, Homologous, Unrelated Donors, Young Adult, Graft vs Host Disease genetics, Polymorphism, Single Nucleotide
- Abstract
Previous studies have identified single-nucleotide polymorphisms (SNPs) associated with the risk of chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation. The current study determined whether these associations could be replicated in large cohorts of donors and recipients. Each SNP was tested with cohorts of patients having the same donor type (HLA-matched related, unrelated, or both) reported in the original publication, and testing was limited to the same genome (recipient or donor) and genetic model (dominant, recessive, or allelic) reported in the original study. The 21 SNPs reported in this study represent 19 genes, and the analysis encompassed 22 SNP association tests. The hazard ratio (HR) point estimates and risk ratio point estimates corresponding to odds ratios in previous studies consistently fall outside the 95% confidence intervals of HR estimates in the current study. Despite the large size of the cohorts available for the current study, the 95% confidence intervals for most HRs did not exclude 1.0. Three SNPs representing CTLA4, HPSE, and IL1R1 showed evidence of association with the risk of chronic GVHD in unrelated donor-recipient pairs from 1 cohort, but none of these associations was replicated when tested in unrelated donor-recipient pairs from an independent cohort. Two SNPs representing CCR6 and FGFR1OP showed possible associations with the risk of chronic GVHD in related donor-recipient pairs but not in unrelated donor-recipient pairs. These results remain to be tested for replication in other cohorts of related donor-recipient pairs., (© 2016 by The American Society of Hematology.)
- Published
- 2016
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21. Genetic risk factors for sclerotic graft-versus-host disease.
- Author
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Inamoto Y, Martin PJ, Flowers ME, Lee SJ, Carpenter PA, Warren EH, Geraghty DE, Lee N, Boeckh MJ, Storer BE, Levine DM, Fan W, Zhao LP, and Hansen JA
- Subjects
- Adolescent, Adult, Aged, B-Lymphocytes metabolism, B-Lymphocytes pathology, Child, Child, Preschool, Cohort Studies, Female, Follow-Up Studies, Genotype, Graft vs Host Disease etiology, Graft vs Host Disease pathology, HLA-DP alpha-Chains chemistry, Haplotypes, Histocompatibility Testing, Humans, Infant, Male, Middle Aged, Prognosis, Protein Conformation, Sclerosis etiology, Sclerosis pathology, Skin Diseases etiology, Skin Diseases pathology, Transplantation, Homologous, Young Adult, Adaptor Proteins, Signal Transducing genetics, Antigens, CD genetics, Antigens, Neoplasm genetics, Graft vs Host Disease diagnosis, HLA-DP alpha-Chains genetics, Hematopoietic Stem Cell Transplantation adverse effects, Membrane Proteins genetics, Polymorphism, Single Nucleotide genetics, Sclerosis diagnosis, Skin Diseases diagnosis
- Abstract
Sclerotic graft-versus-host disease (GVHD) is a distinctive phenotype of chronic GVHD after allogeneic hematopoietic cell transplantation, characterized by fibrosis of skin or fascia. Sclerotic GVHD has clinical and histopathological similarities with systemic sclerosis, an autoimmune disease whose risk is influenced by genetic polymorphisms. We examined 13 candidate single-nucleotide polymorphisms (SNPs) that have a well-documented association with systemic sclerosis to determine whether these SNPs are also associated with the risk of sclerotic GVHD. The study cohort included 847 consecutive patients who were diagnosed with chronic GVHD. Genotyping was performed using microarrays, followed by imputation of unobserved SNPs. The donor rs10516487 (BANK1: B-cell scaffold protein with ankyrin repeats 1) TT genotype was associated with lower risk of sclerotic GVHD (hazard ratio [HR], 0.43; 95% confidence interval [CI], 0.21-0.87; P = .02). Donor and recipient rs2056626 (CD247: T-cell receptor ζ subunit) GG or GT genotypes were associated with higher risk of sclerotic GVHD (HR, 1.57; 95% CI, 1.13-2.18; P = .007 and HR, 1.66; 95% CI, 1.19-2.32; P = .003, respectively). Donor and recipient rs987870 (5'-flanking region of HLA-DPA1) CC genotypes were associated with higher risk of sclerotic GVHD (HR, 2.50; 95% CI, 1.22-5.11; P = .01 and HR, 2.13; 95% CI, 1.00-4.54; P = .05, respectively). In further analyses, the recipient DPA1*01:03∼DPB1*04:01 haplotype and certain amino acid substitutions in the recipient P1 peptide-binding pocket of the HLA-DP heterodimer were associated with risk of sclerotic GVHD. Genetic components associated with systemic sclerosis are also associated with sclerotic GVHD. HLA-DP-mediated antigen presentation, T-cell response, and B-cell activation have important roles in the pathogenic mechanisms of both diseases., (© 2016 by The American Society of Hematology.)
- Published
- 2016
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22. How I treat respiratory viral infections in the setting of intensive chemotherapy or hematopoietic cell transplantation.
- Author
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Waghmare A, Englund JA, and Boeckh M
- Subjects
- Allografts, Humans, Pneumonia, Viral etiology, Respirovirus Infections etiology, Risk Factors, Hematopoietic Stem Cell Transplantation, Pneumonia, Viral drug therapy, Respirovirus, Respirovirus Infections drug therapy, Ribavirin therapeutic use
- Abstract
The widespread use of multiplex molecular diagnostics has led to a significant increase in the detection of respiratory viruses in patients undergoing cytotoxic chemotherapy and hematopoietic cell transplantation (HCT). Respiratory viruses initially infect the upper respiratory tract and then progress to lower respiratory tract disease in a subset of patients. Lower respiratory tract disease can manifest itself as airflow obstruction or viral pneumonia, which can be fatal. Infection in HCT candidates may require delay of transplantation. The risk of progression differs between viruses and immunosuppressive regimens. Risk factors for progression and severity scores have been described, which may allow targeting treatment to high-risk patients. Ribavirin is the only antiviral treatment option for noninfluenza respiratory viruses; however, high-quality data demonstrating its efficacy and relative advantages of the aerosolized versus oral form are lacking. There are significant unmet needs, including data defining the virologic characteristics and clinical significance of human rhinoviruses, human coronaviruses, human metapneumovirus, and human bocavirus, as well as the need for new treatment and preventative options., (© 2016 by The American Society of Hematology.)
- Published
- 2016
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23. Early cytomegalovirus reactivation remains associated with increased transplant-related mortality in the current era: a CIBMTR analysis.
- Author
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Teira P, Battiwalla M, Ramanathan M, Barrett AJ, Ahn KW, Chen M, Green JS, Saad A, Antin JH, Savani BN, Lazarus HM, Seftel M, Saber W, Marks D, Aljurf M, Norkin M, Wingard JR, Lindemans CA, Boeckh M, Riches ML, and Auletta JJ
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Allografts, Antibodies, Viral blood, Antiviral Agents therapeutic use, Bone Marrow Transplantation mortality, Child, Child, Preschool, Cytomegalovirus immunology, Cytomegalovirus Infections complications, Cytomegalovirus Infections drug therapy, Databases, Factual, Disease-Free Survival, Female, Graft vs Host Disease etiology, Graft vs Host Disease mortality, Humans, Infant, Kaplan-Meier Estimate, Leukemia complications, Male, Middle Aged, Myelodysplastic Syndromes complications, Recurrence, Registries, Time Factors, Transplantation Conditioning adverse effects, Young Adult, Bone Marrow Transplantation adverse effects, Cytomegalovirus physiology, Cytomegalovirus Infections virology, Leukemia therapy, Myelodysplastic Syndromes therapy, Virus Activation
- Abstract
Single-center studies have reported an association between early (before day 100) cytomegalovirus (CMV) reactivation and decreased incidence of relapse for acute myeloid leukemia (AML) following allogeneic hematopoietic cell transplantation. To substantiate these preliminary findings, the Center for International Blood and Marrow Transplant Research (CIBMTR) Database was interrogated to analyze the impact of CMV reactivation on hematologic disease relapse in the current era. Data from 9469 patients transplanted with bone marrow or peripheral blood between 2003 and 2010 were analyzed according to 4 disease categories: AML (n = 5310); acute lymphoblastic leukemia (ALL, n = 1883); chronic myeloid leukemia (CML, n = 1079); and myelodysplastic syndrome (MDS, n = 1197). Median time to initial CMV reactivation was 41 days (range, 1-362 days). CMV reactivation had no preventive effect on hematologic disease relapse irrespective of diagnosis. Moreover, CMV reactivation was associated with higher nonrelapse mortality [relative risk [RR] among disease categories ranged from 1.61 to 1.95 and P values from .0002 to <.0001; 95% confidence interval [CI], 1.14-2.61). As a result, CMV reactivation was associated with lower overall survival for AML (RR = 1.27; 95% CI, 1.17-1.38; P <.0001), ALL (RR = 1.46; 95% CI, 1.25-1.71; P <.0001), CML (RR = 1.49; 95% CI, 1.19-1.88; P = .0005), and MDS (RR = 1.31; 95% CI, 1.09-1.57; P = .003). In conclusion, CMV reactivation continues to remain a risk factor for poor posttransplant outcomes and does not seem to confer protection against hematologic disease relapse.
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- 2016
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24. Efficacy of transfusion with granulocytes from G-CSF/dexamethasone-treated donors in neutropenic patients with infection.
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Price TH, Boeckh M, Harrison RW, McCullough J, Ness PM, Strauss RG, Nichols WG, Hamza TH, Cushing MM, King KE, Young JA, Williams E, McFarland J, Holter Chakrabarty J, Sloan SR, Friedman D, Parekh S, Sachais BS, Kiss JE, and Assmann SF
- Subjects
- Anti-Infective Agents therapeutic use, Dexamethasone pharmacology, Glucocorticoids pharmacology, Granulocyte Colony-Stimulating Factor pharmacology, Granulocytes drug effects, Humans, Infections drug therapy, Leukocyte Count, Treatment Outcome, Granulocytes cytology, Infections complications, Leukocyte Transfusion methods, Neutropenia complications, Neutropenia therapy
- Abstract
High-dose granulocyte transfusion therapy has been available for 20 years, yet its clinical efficacy has never been conclusively demonstrated. We report here the results of RING (Resolving Infection in Neutropenia with Granulocytes), a multicenter randomized controlled trial designed to address this question. Eligible subjects were those with neutropenia (absolute neutrophil count <500/μL) and proven/probable/presumed infection. Subjects were randomized to receive either (1) standard antimicrobial therapy or (2) standard antimicrobial therapy plus daily granulocyte transfusions from donors stimulated with granulocyte colony-stimulating factor (G-CSF) and dexamethasone. The primary end point was a composite of survival plus microbial response, at 42 days after randomization. Microbial response was determined by a blinded adjudication panel. Fifty-six subjects were randomized to the granulocyte arm and 58 to the control arm. Transfused subjects received a median of 5 transfusions. Mean transfusion dose was 54.9 × 10(9) granulocytes. Overall success rates were 42% and 43% for the granulocyte and control groups, respectively (P > .99), and 49% and 41%, respectively, for subjects who received their assigned treatments (P = .64). Success rates for granulocyte and control arms did not differ within any infection type. In a post hoc analysis, subjects who received an average dose per transfusion of ≥0.6 × 10(9) granulocytes per kilogram tended to have better outcomes than those receiving a lower dose. In conclusion, there was no overall effect of granulocyte transfusion on the primary outcome, but because enrollment was half that planned, power to detect a true beneficial effect was low. RING was registered at www.clinicaltrials.gov as #NCT00627393., (© 2015 by The American Society of Hematology.)
- Published
- 2015
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25. Idiopathic pneumonia syndrome after hematopoietic cell transplantation: evidence of occult infectious etiologies.
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Seo S, Renaud C, Kuypers JM, Chiu CY, Huang ML, Samayoa E, Xie H, Yu G, Fisher CE, Gooley TA, Miller S, Hackman RC, Myerson D, Sedlak RH, Kim YJ, Fukuda T, Fredricks DN, Madtes DK, Jerome KR, and Boeckh M
- Subjects
- Adolescent, Adult, Aspergillosis diagnosis, Aspergillosis etiology, Aspergillosis microbiology, Aspergillus isolation & purification, Bacterial Infections diagnosis, Bacterial Infections etiology, Bacterial Infections microbiology, Bronchoalveolar Lavage Fluid microbiology, Bronchoalveolar Lavage Fluid virology, Child, Cohort Studies, Female, Humans, Lung microbiology, Lung virology, Lung Injury etiology, Male, Middle Aged, Virus Diseases diagnosis, Virus Diseases etiology, Virus Diseases virology, Young Adult, Hematopoietic Stem Cell Transplantation adverse effects, Lung Injury microbiology, Lung Injury virology
- Abstract
Newer diagnostic methods may link more idiopathic pneumonia syndrome (IPS) cases to an infectious agent. Bronchoalveolar lavage (BAL) samples from 69 hematopoietic cell transplant (HCT) recipients with IPS diagnosed between 1992 and 2006 were tested for 28 pathogens (3 bacteria and 25 viruses) by quantitative polymerase chain reaction and for Aspergillus by galactomannan assay. Research BALs from 21 asymptomatic HCT patients served as controls. Among 69 HCT patients with IPS, 39 (56.5%) had a pathogen detected. The most frequent pathogens were human herpesvirus-6 (HHV-6) (N = 20 [29%]) followed by human rhinovirus (HRV), cytomegalovirus (CMV), and Aspergillus (N = 8 [12%] in each). HHV-6 and HRV were rarely detected in controls, whereas CMV and Aspergillus were occasionally detected with low pathogen load. Patients with pathogens had worse day-100 survival than those without (hazard ratio, 1.88; P = .03). Mortality in patients with only pathogens of "uncertain" significance in lung was similar to that in patients with pathogens of "established" significance. Metagenomic next-generation sequencing did not reveal additional significant pathogens. Our study demonstrated that approximately half of patients with IPS had pathogens detected in BAL, and pathogen detection was associated with increased mortality. Thus, an expanded infection detection panel can significantly increase the diagnostic precision for idiopathic pneumonia., (© 2015 by The American Society of Hematology.)
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- 2015
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26. Clinical disease due to enterovirus D68 in adult hematologic malignancy patients and hematopoietic cell transplant recipients.
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Waghmare A, Pergam SA, Jerome KR, Englund JA, Boeckh M, and Kuypers J
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- Adult, Aged, Base Sequence, DNA, Viral genetics, Female, Humans, Immunocompromised Host, Male, Middle Aged, Rhinovirus genetics, Rhinovirus isolation & purification, Young Adult, Enterovirus D, Human genetics, Enterovirus D, Human isolation & purification, Enterovirus D, Human pathogenicity, Enterovirus Infections complications, Enterovirus Infections diagnosis, Hematologic Neoplasms complications, Hematopoietic Stem Cell Transplantation adverse effects, Respiratory Tract Infections complications, Respiratory Tract Infections diagnosis
- Abstract
The United States Centers for Disease Control and Prevention reported over 1000 cases of severe respiratory disease in pediatric patients associated with enterovirus D68 (EV-D68) in the fall of 2014. We sought to identify and define the clinical burden of disease due to EV-D68 in adult patients with hematologic malignancy or undergoing hematopoietic cell transplant (HCT). Real-time reverse-transcriptase polymerase chain reaction (PCR) for EV-D68 was performed on all respiratory samples positive for human rhinovirus (HRV) or negative for all respiratory viruses by a laboratory-developed respiratory viral PCR panel from August 11, 2014, to November 7, 2014. Presumptive cases were defined as those with an EV-D68 PCR cycle threshold (CT) at least 4 cycles lower than the HRV CT for HRV-positive samples or any EV-D68 CT value for HRV-negative samples. Sequencing of a 150-bp fragment of the 5' noncoding region confirmed EV-D68 in 16 of 506 respiratory samples. Eight patients had a history of hematologic malignancy, and 6 of these had undergone HCT. Presentation ranged from mild upper respiratory symptoms to respiratory failure. EV-D68 can infect adult patients with hematologic malignancy and HCT recipients and may be associated with severe respiratory disease. Current commercial diagnostic assays cannot differentiate EV-D68 from other enteroviruses or HRV, and improved rapid diagnostic tools are needed., (© 2015 by The American Society of Hematology.)
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- 2015
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27. CMV reactivation after allogeneic HCT and relapse risk: evidence for early protection in acute myeloid leukemia.
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Green ML, Leisenring WM, Xie H, Walter RB, Mielcarek M, Sandmaier BM, Riddell SR, and Boeckh M
- Subjects
- Adolescent, Adult, Child, Child, Preschool, Cytomegalovirus Infections etiology, Cytomegalovirus Infections mortality, Female, Follow-Up Studies, Graft vs Host Disease etiology, Graft vs Host Disease mortality, Graft vs Host Disease prevention & control, Humans, Infant, Infant, Newborn, Leukemia, Myelogenous, Chronic, BCR-ABL Positive complications, Leukemia, Myelogenous, Chronic, BCR-ABL Positive prevention & control, Leukemia, Myelogenous, Chronic, BCR-ABL Positive virology, Leukemia, Myeloid, Acute complications, Leukemia, Myeloid, Acute virology, Lymphoma complications, Lymphoma prevention & control, Lymphoma virology, Male, Myelodysplastic Syndromes complications, Myelodysplastic Syndromes prevention & control, Myelodysplastic Syndromes virology, Neoplasm Recurrence, Local mortality, Neoplasm Recurrence, Local virology, Phosphoproteins blood, Precursor Cell Lymphoblastic Leukemia-Lymphoma complications, Precursor Cell Lymphoblastic Leukemia-Lymphoma prevention & control, Precursor Cell Lymphoblastic Leukemia-Lymphoma virology, Prognosis, Retrospective Studies, Risk Factors, Survival Rate, Transplantation Conditioning, Transplantation, Homologous, Viral Matrix Proteins blood, Young Adult, Cytomegalovirus physiology, Cytomegalovirus Infections prevention & control, Hematopoietic Stem Cell Transplantation adverse effects, Leukemia, Myeloid, Acute prevention & control, Neoplasm Recurrence, Local prevention & control, Phosphoproteins immunology, Viral Matrix Proteins immunology, Virus Activation
- Abstract
The association between cytomegalovirus (CMV) reactivation and relapse was evaluated in a large cohort of patients with acute myeloid leukemia (AML) (n = 761), acute lymphoblastic leukemia (ALL) (n = 322), chronic myeloid leukemia (CML) (n = 646), lymphoma (n = 254), and myelodysplastic syndrome (MDS) (n = 371) who underwent allogeneic hematopoietic cell transplantation (HCT) between 1995 and 2005. In multivariable models, CMV pp65 antigenemia was associated with a decreased risk of relapse by day 100 among patients with AML (hazard ratio [HR] = 0.56; 95% confidence interval [CI], 0.3-0.9) but not in patients with ALL, lymphoma, CML, or MDS. The effect appeared to be independent of CMV viral load, acute graft-versus-host disease, or ganciclovir-associated neutropenia. At 1 year after HCT, early CMV reactivation was associated with reduced risk of relapse in all patients, but this did not reach significance for any disease subgroup. Furthermore, CMV reactivation was associated with increased nonrelapse mortality (HR = 1.31; 95% CI, 1.1-1.6) and no difference in overall mortality (HR = 1.05; 95% CI, 0.9-1.3). This report demonstrates a modest reduction in early relapse risk after HCT associated with CMV reactivation in a large cohort of patients without a benefit in overall survival.
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- 2013
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28. Immune reconstitution after anti-thymocyte globulin-conditioned hematopoietic cell transplantation.
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Bosch M, Dhadda M, Hoegh-Petersen M, Liu Y, Hagel LM, Podgorny P, Ugarte-Torres A, Khan FM, Luider J, Auer-Grzesiak I, Mansoor A, Russell JA, Daly A, Stewart DA, Maloney D, Boeckh M, and Storek J
- Subjects
- Adolescent, Adult, Antilymphocyte Serum blood, CD4 Lymphocyte Count, CD4-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes immunology, Cytomegalovirus Infections blood, Cytomegalovirus Infections immunology, Female, Graft vs Host Disease immunology, Histocompatibility Testing, Humans, Male, Middle Aged, Siblings, Young Adult, Antilymphocyte Serum immunology, Hematopoietic Stem Cell Transplantation, Transplantation Conditioning
- Abstract
Background Aims: Anti-thymocyte globulin (ATG) is being used increasingly to prevent graft-versus-host disease (GvHD); however, its impact on immune reconstitution is relatively unknown. We (i) studied immune reconstitution after ATG-conditioned hematopoietic cell transplantation (HCT), (ii) determined the factors influencing the reconstitution, and (iii) compared it with non-ATG-conditioned HCT., Methods: Immune cell subset counts were determined at 1-24 months post-transplant in 125 HCT recipients who received ATG during conditioning. Subset counts were also determined in 46 non-ATG-conditioned patients (similarly treated)., Results: (i) Reconstitution after ATG-conditioned HCT was fast for innate immune cells, intermediate for B cells and CD8 T cells, and very slow for CD4 T cells and invariant natural killer T (iNKT) (iNKT) cells. (ii) Faster reconstitution after ATG-conditioned HCT was associated with a higher number of cells of the same subset transferred with the graft in the case of memory B cells, naive CD4 T cells, naive CD8 T cells, iNKT cells and myeloid dendritic cells; lower recipient age in the case of naive CD4 T cells and naive CD8 T cells; cytomegalovirus recipient seropositivity in the case of memory/effector T cells; an absence of GvHD in the case of naive B cells; lower ATG serum levels in the case of most T-cell subsets, including iNKT cells; and higher ATG levels in the case of NK cells and B cells. (iii) Compared with non-ATG-conditioned HCT, reconstitution after ATG-conditioned HCT was slower for CD4 T cells, and faster for NK cells and B cells., Conclusions: ATG worsens the reconstitution of CD4 T cells but improves the reconstitution of NK and B cells.
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- 2012
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29. Effect of MHC and non-MHC donor/recipient genetic disparity on the outcome of allogeneic HCT.
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Warren EH, Zhang XC, Li S, Fan W, Storer BE, Chien JW, Boeckh MJ, Zhao LP, Martin PJ, and Hansen JA
- Subjects
- Humans, Prognosis, Transplantation, Homologous, Graft vs Host Disease genetics, Graft vs Host Disease immunology, Hematopoietic Stem Cell Transplantation, Histocompatibility genetics, Major Histocompatibility Complex genetics, Major Histocompatibility Complex immunology, Tissue Donors
- Abstract
The outcome of allogeneic hematopoietic cell transplantation is influenced by donor/recipient genetic disparity at loci both inside and outside the MHC on chromosome 6p. Although disparity at loci within the MHC is the most important risk factor for the development of severe GVHD, disparity at loci outside the MHC that encode minor histocompatibility (H) antigens can elicit GVHD and GVL activity in donor/recipient pairs who are otherwise genetically identical across the MHC. Minor H antigens are created by sequence and structural variations within the genome. The enormous variation that characterizes the human genome suggests that the total number of minor H loci is probably large and ensures that all donor/recipient pairs, despite selection for identity at the MHC, will be mismatched for many minor H antigens. In addition to mismatch at minor H loci, unrelated donor/recipient pairs exhibit genetic disparity at numerous loci within the MHC, particularly HLA-DP, despite selection for identity at HLA-A, -B, -C, and -DRB1. Disparity at HLA-DP exists in 80% of unrelated pairs and clearly influences the outcome of unrelated hematopoietic cell transplantation; the magnitude of this effect probably exceeds that associated with disparity at any locus outside the MHC.
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- 2012
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30. Evaluation of published single nucleotide polymorphisms associated with acute GVHD.
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Chien JW, Zhang XC, Fan W, Wang H, Zhao LP, Martin PJ, Storer BE, Boeckh M, Warren EH, and Hansen JA
- Subjects
- Acute Disease, Adult, Alleles, Female, Genotype, Humans, Male, Middle Aged, Transplantation, Homologous, Genetic Predisposition to Disease, Glucuronidase genetics, Graft vs Host Disease genetics, Hematopoietic Stem Cell Transplantation, Interleukin-10 genetics, Interleukin-2 genetics, Interleukin-6 genetics, Methylenetetrahydrofolate Reductase (NADPH2) genetics, Polymorphism, Single Nucleotide
- Abstract
Candidate genetic associations with acute GVHD (aGVHD) were evaluated with the use of genotyped and imputed single-nucleotide polymorphism data from genome-wide scans of 1298 allogeneic hematopoietic cell transplantation (HCT) donors and recipients. Of 40 previously reported candidate SNPs, 6 were successfully genotyped, and 10 were imputed and passed criteria for analysis. Patient and donor genotypes were assessed for association with grades IIb-IV and III-IV aGVHD, stratified by donor type, in univariate and multivariate allelic, recessive and dominant models. Use of imputed genotypes to replicate previous IL10 associations was validated. Similar to previous publications, the IL6 donor genotype for rs1800795 was associated with a 20%-50% increased risk for grade IIb-IV aGVHD after unrelated HCT in the allelic (adjusted P = .011) and recessive (adjusted P = .0013) models. The donor genotype was associated with a 60% increase in risk for grade III-IV aGVHD after related HCT (adjusted P = .028). Other associations were found for IL2, CTLA4, HPSE, and MTHFR but were inconsistent with original publications. These results illustrate the advantages of using imputed single-nucleotide polymorphism data in genetic analyses and demonstrate the importance of validation in genetic association studies.
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- 2012
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31. Maribavir and human cytomegalovirus-what happened in the clinical trials and why might the drug have failed?
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Marty FM and Boeckh M
- Subjects
- Animals, Clinical Trials as Topic standards, Clinical Trials, Phase II as Topic methods, Clinical Trials, Phase II as Topic standards, Clinical Trials, Phase III as Topic methods, Clinical Trials, Phase III as Topic standards, Cytomegalovirus Infections etiology, Humans, Randomized Controlled Trials as Topic methods, Randomized Controlled Trials as Topic standards, Stem Cell Transplantation adverse effects, Antiviral Agents pharmacology, Benzimidazoles pharmacology, Clinical Trials as Topic methods, Cytomegalovirus isolation & purification, Cytomegalovirus Infections prevention & control, Ribonucleosides pharmacology, Stem Cell Transplantation methods
- Abstract
We summarize the history of the clinical drug development of maribavir for its use as prophylaxis in stem-cell transplant recipients. We highlight key aspects in the design and interpretation of the results of the dose escalation phase II maribavir study that may have contributed to the negative findings on the phase III trials. We discuss key aspects of study design that should be considered in the study of new interventions needed to advance the prevention and treatment of CMV in transplant recipients., (Copyright © 2011. Published by Elsevier B.V.)
- Published
- 2011
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32. Intensive strategy to prevent CMV disease in seropositive umbilical cord blood transplant recipients.
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Milano F, Pergam SA, Xie H, Leisenring WM, Gutman JA, Riffkin I, Chow V, Boeckh MJ, and Delaney C
- Subjects
- Adolescent, Adult, Antiviral Agents adverse effects, Child, Cohort Studies, Cord Blood Stem Cell Transplantation methods, Cytomegalovirus Infections diagnosis, Cytomegalovirus Infections epidemiology, Female, Humans, Immunosuppressive Agents therapeutic use, Incidence, Male, Middle Aged, Proportional Hazards Models, Risk Factors, Secondary Prevention, Seroepidemiologic Studies, Viral Load drug effects, Young Adult, Cord Blood Stem Cell Transplantation adverse effects, Cytomegalovirus Infections prevention & control, Ganciclovir administration & dosage
- Abstract
Seropositive umbilical cord blood transplant (UCBT) recipients are at increased risk for CMV complications. To reduce CMV complications, we adopted an intensive strategy that consisted of ganciclovir administered before transplantation (5 mg/kg intravenously daily from day -8 to day -2), high-dose acyclovir (2 g, 3 times daily) after transplantation, and biweekly monitoring with a serum CMV PCR for preemptive therapy. Hazard rates and cumulative incidence of CMV complications along with days treated were compared in high-risk CMV-seropositive UCBT recipients who received the intensive strategy and a historical cohort who received a standard strategy. Of 72 seropositive patients, 29 (40%) received standard prophylaxis and 43 (60%) the new intensive approach. The hazard rate (HR) for CMV reactivation was lower for patients receiving the intensive strategy (HR 0.27, 95% confidence interval 0.15-0.48; P < .001) and led to fewer cases of CMV disease by 1 year (HR 0.11, 95% confidence interval 0.02-0.53; P = .006). In patients who reactivated, the intensive strategy also led to fewer days on CMV-specific antiviral therapy (median 42% [interquartile range 21-63] vs 70% [interquartile range 54-83], P < .001). Use of an intensive CMV prevention strategy in high-risk CMVseropositive UCBT recipients results in a significant decrease in CMV reactivation and disease.
- Published
- 2011
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33. Differences in clinical outcomes after 2009 influenza A/H1N1 and seasonal influenza among hematopoietic cell transplant recipients.
- Author
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Choi SM, Boudreault AA, Xie H, Englund JA, Corey L, and Boeckh M
- Subjects
- Adolescent, Adult, Antiviral Agents therapeutic use, Female, Humans, Influenza, Human epidemiology, Male, Middle Aged, Retrospective Studies, Young Adult, Hematopoietic Stem Cell Transplantation, Influenza A Virus, H1N1 Subtype physiology, Influenza, Human complications, Influenza, Human virology, Transplantation
- Abstract
It is not known whether pandemic 2009 influenza A/H1N1 (2009 H1N1) leads to more serious disease than seasonal influenza in hematopoietic cell transplant (HCT) recipients. In a retrospective study in HCT recipients with virologically proven influenza virus infection, a total of 161 HCT recipients (18 2009 H1N1, 103 seasonal influenza A, and 40 seasonal influenza B) were analyzed. In multivariable analyses, more patients with 2009 H1N1 had lower respiratory tract disease (LRD), hypoxemia, and prolonged viral shedding compared with seasonal influenza A. Seasonal influenza A and B outcomes were similar. There was no difference in overall and influenza-associated mortality among influenza virus types. Both early and delayed administration of antiviral therapy was shown to be beneficial in terms of decreased rates of development of LRD, although earlier intervention appeared to be more effective. Profound lymphopenia and lack of early antiviral therapy were associated significantly with LRD, hypoxemia, and death. High-dose corticosteroid treatment (≥ 1 mg/kg) given at the time of influenza diagnosis was associated with a reduced risk for mechanical ventilation. Thus, our data suggest that infection with 2009 influenza A/H1N1 resulted in more severe respiratory disease in HCT recipients compared with seasonal influenza.
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- 2011
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34. HHV-6 reactivation and its effect on delirium and cognitive functioning in hematopoietic cell transplantation recipients.
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Zerr DM, Fann JR, Breiger D, Boeckh M, Adler AL, Xie H, Delaney C, Huang ML, Corey L, and Leisenring WM
- Subjects
- Adult, Cognition Disorders epidemiology, Delirium epidemiology, Female, Herpesvirus 6, Human physiology, Humans, Male, Middle Aged, Neuropsychological Tests, Roseolovirus Infections epidemiology, Roseolovirus Infections virology, Transplantation, Young Adult, Cognition Disorders virology, Delirium virology, Hematopoietic Stem Cell Transplantation adverse effects, Roseolovirus Infections complications, Virus Activation physiology
- Abstract
Human herpesvirus 6 (HHV-6) is detected in the plasma of approximately 40% of patients undergoing hematopoietic cell transplantation (HCT) and sporadically causes encephalitis in this population. The effect of HHV-6 reactivation on central nervous system function has not been fully characterized. This prospective study aimed to evaluate associations between HHV-6 reactivation and central nervous system dysfunction after allogeneic HCT. Patients were enrolled before HCT. Plasma samples were tested for HHV-6 at baseline and twice weekly after transplantation until day 84. Delirium was assessed at baseline, 3 times weekly until day 56, and weekly on days 56 to 84 using a validated instrument. Neurocognitive testing was performed at baseline and at approximately day 84. HHV-6 was detected in 111 (35%) of the 315 included patients. Patients with HHV-6 were more likely to develop delirium (adjusted odds ratio = 2.5; 95% confidence interval, 1.2-5.3) and demonstrate neurocognitive decline (adjusted odds ratio = 2.6; 95% confidence interval, 1.1-6.2) in the first 84 days after HCT. Cord blood and unrelated transplantation increased risk of HHV-6 reactivation. These data provide the basis to conduct a randomized clinical trial to determine whether prevention of HHV-6 reactivation will reduce neurocognitive morbidity in HCT recipients.
- Published
- 2011
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35. Randomized, double-blind trial of fluconazole versus voriconazole for prevention of invasive fungal infection after allogeneic hematopoietic cell transplantation.
- Author
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Wingard JR, Carter SL, Walsh TJ, Kurtzberg J, Small TN, Baden LR, Gersten ID, Mendizabal AM, Leather HL, Confer DL, Maziarz RT, Stadtmauer EA, Bolaños-Meade J, Brown J, Dipersio JF, Boeckh M, and Marr KA
- Subjects
- Adolescent, Adult, Aged, Antifungal Agents, Aspergillosis drug therapy, Aspergillosis prevention & control, Child, Child, Preschool, Disease-Free Survival, Double-Blind Method, Drug Monitoring, Fluconazole adverse effects, Galactose analogs & derivatives, Hematologic Neoplasms mortality, Hematologic Neoplasms therapy, Hematopoietic Stem Cell Transplantation mortality, Humans, Mannans blood, Middle Aged, Mycoses drug therapy, Myeloablative Agonists therapeutic use, Survival Rate, Transplantation, Homologous, Young Adult, Fluconazole administration & dosage, Hematopoietic Stem Cell Transplantation adverse effects, Mycoses prevention & control
- Abstract
Invasive fungal infection (IFI) is a serious threat after allogeneic hematopoietic cell transplant (HCT). This multicenter, randomized, double-blind trial compared fluconazole (N = 295) versus voriconazole (N = 305) for the prevention of IFI in the context of a structured fungal screening program. Patients undergoing myeloablative allogeneic HCT were randomized before HCT to receive study drugs for 100 days, or for 180 days in higher-risk patients. Serum galactomannan was assayed twice weekly for 60 days, then at least weekly until day 100. Positive galactomannan or suggestive signs triggered mandatory evaluation for IFI. The primary endpoint was freedom from IFI or death (fungal-free survival; FFS) at 180 days. Despite trends to fewer IFIs (7.3% vs 11.2%; P = .12), Aspergillus infections (9 vs 17; P = .09), and less frequent empiric antifungal therapy (24.1% vs 30.2%, P = .11) with voriconazole, FFS rates (75% vs 78%; P = .49) at 180 days were similar with fluconazole and voriconazole, respectively. Relapse-free and overall survival and the incidence of severe adverse events were also similar. This study demonstrates that in the context of intensive monitoring and structured empiric antifungal therapy, 6-month FFS and overall survival did not differ in allogeneic HCT recipients given prophylactic fluconazole or voriconazole. This trial was registered at www.clinicaltrials.gov as NCT00075803.
- Published
- 2010
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36. Immune monitoring with iTAg MHC Tetramers for prediction of recurrent or persistent cytomegalovirus infection or disease in allogeneic hematopoietic stem cell transplant recipients: a prospective multicenter study.
- Author
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Gratama JW, Boeckh M, Nakamura R, Cornelissen JJ, Brooimans RA, Zaia JA, Forman SJ, Gaal K, Bray KR, Gasior GH, Boyce CS, Sullivan LA, and Southwick PC
- Subjects
- Adolescent, Adult, Aged, CD4-Positive T-Lymphocytes cytology, CD4-Positive T-Lymphocytes immunology, Cytomegalovirus Infections diagnosis, Cytomegalovirus Infections etiology, Female, Flow Cytometry, HLA-A Antigens genetics, HLA-A Antigens immunology, HLA-A1 Antigen, HLA-B Antigens genetics, HLA-B Antigens immunology, HLA-B7 Antigen, Hematopoietic Stem Cell Transplantation adverse effects, Histocompatibility Testing, Humans, Longitudinal Studies, Male, Middle Aged, Postoperative Complications diagnosis, Postoperative Complications etiology, Prognosis, Prospective Studies, Reproducibility of Results, Transplantation, Homologous, Young Adult, Cytomegalovirus Infections immunology, Hematopoietic Stem Cell Transplantation methods, Monitoring, Immunologic methods, Postoperative Complications immunology
- Abstract
Cytomegalovirus (CMV) infection is an important cause of morbidity and mortality in hematopoietic stem cell transplant recipients despite the introduction of posttransplantation viral monitoring and preemptive antiviral therapy. We evaluated the use of HLA class I tetramers in monitoring CMV-specific T-cell recovery to predict patients at risk for CMV-related complications. This prospective multicenter clinical trial obtained nearly 1400 tetramer/allele results in more than 800 biweekly blood samples from 83 patients monitored for 1 year after transplantation. Major HLA types were included (A*0101, A*0201, B*0702, B*0801, B*3501). iTAg MHC Tetramers (Beckman Coulter) were used to enumerate CMV-specific CD8(+) T cells by flow cytometry using a single-platform absolute counting method. Assay variability was 8% or less and results were available within 3 hours. Delayed recovery of CMV-specific T cells (< 7 cells/μL in all blood samples during the first 65 days after transplantation) was found to be a significant risk factor for CMV-related complications; these patients were more likely to develop recurrent or persistent CMV infection (relative risk 2.6, CI 1.2-5.8, P = .01) than patients showing rapid recovery, which was associated with protection from CMV-related complications (P = .004). CMV tetramer-based immune monitoring, in conjunction with virologic monitoring, can be an important new tool to assess risk of CMV-related complications and to guide preemptive therapeutic choices.
- Published
- 2010
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37. Human rhinovirus and coronavirus detection among allogeneic hematopoietic stem cell transplantation recipients.
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Milano F, Campbell AP, Guthrie KA, Kuypers J, Englund JA, Corey L, and Boeckh M
- Subjects
- Adolescent, Adult, Aged, Animals, Cells, Cultured, Child, Child, Preschool, Chlorocebus aethiops, Coronaviridae Infections diagnosis, Female, Humans, Incidence, Infant, Macaca mulatta, Male, Middle Aged, Picornaviridae Infections diagnosis, Transplantation, Homologous, Young Adult, Coronaviridae Infections epidemiology, Coronavirus isolation & purification, Hematopoietic Stem Cell Transplantation statistics & numerical data, Picornaviridae Infections epidemiology, Rhinovirus isolation & purification
- Abstract
Little is known about clinical and virologic manifestations of rhinovirus (HRV) and coronavirus (HCoV) infections after hematopoietic cell transplantation (HCT). We performed surveillance for 1 year and describe the natural history of these infections during the first 100 days after allogeneic HCT, when symptom surveys and upper respiratory samples were collected weekly. Samples were tested using RT-PCR for HRVs and HCoVs (OC43, 229E, HKU1, and NL63). Among 215 patients, 64 (30%) patients had 67 infections. Day 100 cumulative incidence estimate was 22.3% for HRV and 11.1% for HCoV. Median duration of viral shedding was 3 weeks; prolonged shedding of at least 3 months occurred in 6 of 45 patients with HRV and 3 of 22 with HCoV. Six patients with HRV and 9 with HCoV were asymptomatic. HRV infection was associated with rhinorrhea, congestion, postnasal drip, sputum, and cough; HCoV infection was not associated with respiratory symptoms or hepatic dysfunction. Lower respiratory infection developed in 2 patients with HRV before day 100, and 1 each with HRV and HCoV after day 100. HRV and HCoV infections are common in the first 100 days after HCT, viral shedding lasts more than 3 weeks in half, and lower respiratory infection is rare.
- Published
- 2010
- Full Text
- View/download PDF
38. How I treat influenza in patients with hematologic malignancies.
- Author
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Casper C, Englund J, and Boeckh M
- Subjects
- Comorbidity, Disease Outbreaks, Humans, Infection Control, Influenza, Human prevention & control, Antiviral Agents therapeutic use, Hematologic Neoplasms epidemiology, Influenza A Virus, H1N1 Subtype, Influenza, Human drug therapy, Influenza, Human epidemiology
- Abstract
The 2009 H1N1 influenza pandemic has heightened the interest of clinicians for options in the prevention and management of influenza virus infection in immunocompromised patients. Even before the emergence of the novel 2009 H1N1 strain, influenza disease was a serious complication in patients with hematologic malignancies receiving chemotherapy or undergoing hematopoietic cell transplantation. Here we review the clinical manifestations of seasonal and 2009 H1N1 influenza and discuss current diagnosis, antiviral treatment, and prophylaxis options. We also summarize infection control and vaccination strategies for patients, family members, and caregivers.
- Published
- 2010
- Full Text
- View/download PDF
39. How we treat cytomegalovirus in hematopoietic cell transplant recipients.
- Author
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Boeckh M and Ljungman P
- Subjects
- Animals, Antiviral Agents therapeutic use, Cytomegalovirus Infections blood, Cytomegalovirus Infections diagnosis, Drug Resistance, Viral drug effects, Humans, Risk Factors, Cytomegalovirus Infections drug therapy, Cytomegalovirus Infections prevention & control, Hematopoietic Stem Cell Transplantation
- Abstract
Cytomegalovirus (CMV) continues to cause major complications after hematopoietic cell transplantation (HCT). Over the past decade, most centers have adopted preemptive antiviral treatment or prophylaxis strategies to prevent CMV disease. Both strategies are effective but also have shortcomings with presently available drugs. Here, we review aspects of CMV treatment and prevention in HCT recipients, including currently used drugs and diagnostics, ways to optimize preemptive therapy strategies with quantitative polymerase chain reaction assays, the use of prophylaxis, management of CMV disease caused by wild-type or drug-resistant strains, and future strategies.
- Published
- 2009
- Full Text
- View/download PDF
40. Initial therapy of acute graft-versus-host disease with low-dose prednisone does not compromise patient outcomes.
- Author
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Mielcarek M, Storer BE, Boeckh M, Carpenter PA, McDonald GB, Deeg HJ, Nash RA, Flowers ME, Doney K, Lee S, Marr KA, Furlong T, Storb R, Appelbaum FR, and Martin PJ
- Subjects
- Acute Disease, Adolescent, Adult, Aged, Dose-Response Relationship, Drug, Female, Glucocorticoids administration & dosage, Hematologic Neoplasms therapy, Humans, Male, Middle Aged, Retrospective Studies, Transplantation Conditioning methods, Transplantation, Homologous, Treatment Outcome, Young Adult, Graft vs Host Disease drug therapy, Hematopoietic Stem Cell Transplantation adverse effects, Prednisone administration & dosage
- Abstract
We hypothesized that initial treatment of acute graft-versus-host disease (GVHD) with low-dose glucocorticoids (prednisone-equivalent dose of 1 mg/kg per day) instead of standard-dose glucocorticoids (prednisone-equivalent dose of 2 mg/kg per day) does not compromise major transplantation outcomes. We retrospectively analyzed outcomes among 733 patients who received transplants between 2000 and 2005 according to initial treatment with low-dose (n=347) versus standard-dose (n=386) systemic glucocorticoids. The mean cumulative prednisone-equivalent doses at day 100 after starting treatment were 44 and 87 mg/kg for patients given low-dose and standard-dose glucocorticoids, respectively. Adjusted outcomes between the groups given low-dose versus standard-dose glucocorticoids were not statistically significantly different: overall mortality (hazard ratio [HR], 1.10; 95% confidence interval [CI], 0.9-1.4), relapse (HR, 1.22; 95% CI, 0.9-1.7), nonrelapse mortality (HR, 1.06; 95% CI, 0.8-1.5). The small number of patients with grades III/IV acute GVHD at onset precluded definitive conclusions for this subgroup. In multivariate analysis, the risks of invasive fungal infections (HR, 0.59; 95% CI, 0.3-1.0) and the duration of hospitalization (odds ratio, 0.62; 95% CI, 0.4-0.9) were reduced in the low-dose prednisone group. We conclude that initial treatment with low-dose glucocorticoids for patients with grades I-II GVHD did not compromise disease control or mortality and was associated with decreased toxicity.
- Published
- 2009
- Full Text
- View/download PDF
41. Maribavir prophylaxis for prevention of cytomegalovirus infection in allogeneic stem cell transplant recipients: a multicenter, randomized, double-blind, placebo-controlled, dose-ranging study.
- Author
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Winston DJ, Young JA, Pullarkat V, Papanicolaou GA, Vij R, Vance E, Alangaden GJ, Chemaly RF, Petersen F, Chao N, Klein J, Sprague K, Villano SA, and Boeckh M
- Subjects
- Adult, Antiviral Agents adverse effects, Antiviral Agents blood, Benzimidazoles adverse effects, Benzimidazoles blood, Dose-Response Relationship, Drug, Double-Blind Method, Female, Humans, Male, Middle Aged, Nausea chemically induced, Ribonucleosides adverse effects, Ribonucleosides blood, Taste Disorders chemically induced, Transplantation, Homologous, Vomiting chemically induced, Antiviral Agents administration & dosage, Benzimidazoles administration & dosage, Cytomegalovirus Infections prevention & control, Ribonucleosides administration & dosage, Stem Cell Transplantation
- Abstract
The anti-cytomegalovirus (CMV) activity and safety of oral maribavir in CMV-seropositive allogeneic stem-cell transplant recipients were evaluated in a randomized, double-blind, placebo-controlled, dose-ranging study. After engraftment, 111 patients were randomized to receive CMV prophylaxis with maribavir (100 mg twice daily, 400 mg once daily, or 400 mg twice daily) or placebo. Within the first 100 days after transplantation, the incidence of CMV infection based on CMV pp65 antigenemia was lower in each of the respective maribavir groups (15%, P = .046; 19%, P = .116; 15%, P = .053) compared with placebo (39%). Similarly, the incidence of CMV infection based on plasma CMV DNA was lower in each of the respective maribavir groups (7%, P = .001; 11%, P = .007; 19%, P = .038) compared with placebo (46%). Anti-CMV therapy was also used less often in patients receiving each respective dose of maribavir (15%, P = .001; 30%, P = .051; 15%, P = .002) compared with placebo (57%). There were 3 cases of CMV disease in placebo patients but none in the maribavir patients. Adverse events, mostly taste disturbance, nausea, and vomiting, were more frequent with maribavir. Maribavir had no adverse effect on neutrophil or platelet counts. These results show that maribavir can reduce the incidence of CMV infection and, unlike ganciclovir, does not cause myelosuppression.
- Published
- 2008
- Full Text
- View/download PDF
42. Lipopolysaccharide binding protein promoter variants influence the risk for Gram-negative bacteremia and mortality after allogeneic hematopoietic cell transplantation.
- Author
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Chien JW, Boeckh MJ, Hansen JA, and Clark JG
- Subjects
- Adult, Case-Control Studies, Cohort Studies, DNA genetics, Female, Genotype, Hematopoietic Stem Cell Transplantation mortality, Humans, Male, Middle Aged, Neutropenia epidemiology, Polymorphism, Single Nucleotide, Retrospective Studies, Transplantation, Homologous, Acute-Phase Proteins genetics, Carrier Proteins genetics, Genetic Variation, Gram-Negative Bacterial Infections epidemiology, Hematopoietic Stem Cell Transplantation adverse effects, Membrane Glycoproteins genetics, Transcription, Genetic
- Abstract
Lipopolysaccharide binding protein (LBP) function is dependent on circulating LBP levels. Disturbance of LBP transcription regulation may influence the risk for clinical events. In a nested case-control study using a single nucleotide polymorphism haplotype tagging (tagSNP) approach, we assessed whether genetic variation in the LBP gene influences the risk for Gram-negative (GN) bacteremia after allogeneic hematopoietic cell transplantation (HCT), then validated the association in a prospective cohort by correlating genetic variation with basal serum LBP levels and mortality. Presence of the tagSNP 6878 C allele among patients was associated with a 2-fold higher risk for GN bacteremia (odds ratio = 2.15; 95% confidence interval [CI], 1.31-3.52, P = .002). TagSNP 6878 was in strong linkage disequilibrium with 3 SNPs in the LBP promoter, one of which was SNP 1683 (r(2) = 0.8), located in a CAAT box that regulates LBP promoter efficiency. SNP 1683 was associated with higher median basal serum LBP levels (TT 8.07 microg/mL; TC 10.40 microg/mL; CC 17.39 microg/mL; P = .002), and a 5-fold increase in GN bacteremia related mortality after HCT (hazard ratio = 4.83; 95% CI, 1.38-16.75, P = .013). These data suggest that transcriptional regulation of the LBP gene contributes to the risk for developing GN bacteremia and death after HCT.
- Published
- 2008
- Full Text
- View/download PDF
43. One-year acyclovir prophylaxis for preventing varicella-zoster virus disease after hematopoietic cell transplantation: no evidence of rebound varicella-zoster virus disease after drug discontinuation.
- Author
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Erard V, Guthrie KA, Varley C, Heugel J, Wald A, Flowers ME, Corey L, and Boeckh M
- Subjects
- Adolescent, Adult, Aged, Child, Child, Preschool, Female, Herpes Zoster epidemiology, Herpes Zoster immunology, Humans, Immunocompromised Host, Infant, Male, Middle Aged, Simplexvirus drug effects, Simplexvirus physiology, Time Factors, Acyclovir administration & dosage, Antiviral Agents administration & dosage, Hematopoietic Stem Cell Transplantation adverse effects, Herpes Zoster prevention & control, Virus Activation drug effects
- Abstract
No consensus exists on whether acyclovir prophylaxis should be given for varicella-zoster virus (VZV) prophylaxis after hematopoietic cell transplantation because of the concern of "rebound" VZV disease after discontinuation of prophylaxis. To determine whether rebound VZV disease is an important clinical problem and whether prolonging prophylaxis beyond 1 year is beneficial, we examined 3 sequential cohorts receiving acyclovir from day of transplantation until engraftment for prevention of herpes simplex virus reactivation (n = 932); acyclovir or valacyclovir 1 year (n = 1117); or acyclovir/valacyclovir for at least 1 year or longer if patients remained on immunosuppressive drugs (n = 586). In multivariable statistical models, prophylaxis given for 1 year significantly reduced VZV disease (P < .001) without evidence of rebound VZV disease. Continuation of prophylaxis beyond 1 year in allogeneic recipients who remained on immunosuppressive drugs led to a further reduction in VZV disease (P = .01) but VZV disease developed in 6.1% during the second year while receiving this strategy. In conclusion, acyclovir/valacyclovir prophylaxis given for 1 year led to a persistent benefit after drug discontinuation and no evidence of a rebound effect. To effectively prevent VZV disease in long-term hematopoietic cell transplantation survivors, additional approaches such as vaccination will probably be required.
- Published
- 2007
- Full Text
- View/download PDF
44. Respiratory virus infection among hematopoietic cell transplant recipients: evidence for asymptomatic parainfluenza virus infection.
- Author
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Peck AJ, Englund JA, Kuypers J, Guthrie KA, Corey L, Morrow R, Hackman RC, Cent A, and Boeckh M
- Subjects
- Adolescent, Adult, Aged, Animals, Cell Line, Child, Child, Preschool, Chlorocebus aethiops, Female, Follow-Up Studies, Hematologic Neoplasms therapy, Hematologic Neoplasms virology, Humans, Incidence, Infant, Infection Control, Male, Middle Aged, Paramyxoviridae Infections diagnosis, Paramyxoviridae Infections genetics, Paramyxoviridae Infections virology, Prospective Studies, RNA Viruses genetics, RNA, Viral analysis, RNA, Viral genetics, Respiratory Tract Infections diagnosis, Respiratory Tract Infections genetics, Respiratory Tract Infections virology, Reverse Transcriptase Polymerase Chain Reaction, Sentinel Surveillance, Transplantation, Autologous, Transplantation, Homologous, Virus Cultivation, Hematopoietic Stem Cell Transplantation, Paramyxoviridae Infections epidemiology, Respiratory Tract Infections epidemiology
- Abstract
The incidence of respiratory virus infection after hematopoietic cell transplantation (HCT) has probably been underestimated with conventional testing methods in symptomatic patients. This prospective study assessed viral infection episodes by testing weekly respiratory samples collected from HCT recipients, with and without symptoms reported by questionnaire, for 100 days after HCT. Samples were tested by culture and direct fluorescent antibody testing for respiratory syncytial virus (RSV), parainfluenza virus (PIV), and influenza A and B, and by quantitative reverse transcription-polymerase chain reaction for RSV, PIV, influenza A and B, and metapneumovirus (MPV). Of 122 patients, 30 (25%) had 32 infection episodes caused by RSV (5), PIV (17), MPV (6), influenza (3), RSV, or influenza (1). PIV, with a cumulative incidence estimate of 17.9%, was the only virus for which asymptomatic infection was detected. Lower virus copy number in patients with no or one symptom compared with 2 or more symptoms was found for all viruses in all patients (P < .001), with PIV infection having a similar virus-specific comparison (P = .004). Subclinical infection with PIV may help explain why infection-control programs that emphasize symptoms are effective against RSV and influenza but often not against PIV.
- Published
- 2007
- Full Text
- View/download PDF
45. Long-term acyclovir for prevention of varicella zoster virus disease after allogeneic hematopoietic cell transplantation--a randomized double-blind placebo-controlled study.
- Author
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Boeckh M, Kim HW, Flowers ME, Meyers JD, and Bowden RA
- Subjects
- Adolescent, Adult, Aged, Child, Chronic Disease, Cytomegalovirus immunology, Cytomegalovirus Infections immunology, Cytomegalovirus Infections prevention & control, Double-Blind Method, Female, Follow-Up Studies, Graft vs Host Disease etiology, Graft vs Host Disease immunology, Graft vs Host Disease virology, Hematologic Neoplasms complications, Hematologic Neoplasms immunology, Hematologic Neoplasms mortality, Herpes Simplex immunology, Herpes Simplex prevention & control, Herpes Zoster etiology, Herpes Zoster immunology, Herpes Zoster mortality, Humans, Male, Middle Aged, Simplexvirus immunology, T-Lymphocytes, Helper-Inducer immunology, Transplantation, Homologous, Virus Activation drug effects, Acyclovir administration & dosage, Hematologic Neoplasms therapy, Hematopoietic Stem Cell Transplantation, Herpes Zoster prevention & control
- Abstract
Varicella-zoster virus (VZV) disease occurs in 30% of allogeneic hematopoietic cell transplant recipients who had a history of VZV infection. A safe and effective prevention strategy has not been established. In a double-blind controlled trial, 77 hematopoietic cell transplant recipients at risk for VZV reactivation were randomized to acyclovir 800 mg twice daily or placebo given from 1 to 2 months until 1 year after transplantation. VZV disease at 1 year was the primary end point; VZV disease after discontinuation of prophylaxis, VZV-specific T-cell immunity, herpes simplex virus (HSV) infection, cytomegalovirus (CMV) disease, survival, and safety were secondary end points. Acyclovir significantly reduced VZV infections at 1 year after transplantation (HR, 0.16; 95% CI, 0.035-0.74; P = .006). In the post-intervention observation period, this difference was not statistically significant (2 years: HR, 0.52; 95% CI, 0.21-1.3; 5 years: HR, 0.76; 95% CI, 0.36-1.6). There was no statistically significant difference in reconstitution of VZV-specific T-helper cell responses, HSV infections, CMV disease, chronic graft-versus-host disease, and overall survival between the groups. Acyclovir was well tolerated. Post-study VZV disease predominantly occurred in patients with continued need for systemic immunosuppression. In conclusion, acyclovir effectively and safely prevents VZV disease during the first year after hematopoietic cell transplantation. Periods of prophylaxis longer than 12 months may be beneficial for those hematopoietic cell transplant recipients on continued immune suppression.
- Published
- 2006
- Full Text
- View/download PDF
46. BK DNA viral load in plasma: evidence for an association with hemorrhagic cystitis in allogeneic hematopoietic cell transplant recipients.
- Author
-
Erard V, Kim HW, Corey L, Limaye A, Huang ML, Myerson D, Davis C, and Boeckh M
- Subjects
- Adolescent, Adult, Case-Control Studies, Child, Cystitis etiology, DNA, Viral blood, Female, Hemorrhage, Humans, Male, Middle Aged, Odds Ratio, Polymerase Chain Reaction, Polyomavirus Infections complications, Transplantation, Homologous, Tumor Virus Infections complications, Viremia complications, BK Virus isolation & purification, Cystitis virology, Hematopoietic Stem Cell Transplantation adverse effects, Viral Load methods
- Abstract
We performed a case-control study to determine the association of BK plasma viremia with hemorrhagic cystitis (HC) in hematopoietic cell transplant (HCT) recipients. Thirty cases of HC (14 of which occurred after platelet engraftment with documented BK viruria [BK-HC]) were compared with matched controls. Weekly plasma samples were tested for BK virus DNA by polymerase chain reaction (PCR). BK viremia detected before or during the disease was independently associated with HC (adjusted odds ratio = 30, P < .001); BK viremia was even important before clinical symptoms of HC occurred (odds ratio = 11, P < .001). Cases of HC and BK-HC had a significantly higher peak of BK plasma viral load than controls. BK virus was detected by in situ hybridization in bladder biopsies of 2 cases with severe HC and long-lasting BK viremia. BK virus seems to play a role in the development of HC and quantitative detection of BK DNA in plasma appears to be a marker of BK virus disease in HCT recipients.
- Published
- 2005
- Full Text
- View/download PDF
47. Polyomavirus nephropathy in native kidneys of non-renal transplant recipients.
- Author
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Limaye AP, Smith KD, Cook L, Groom DA, Hunt NC, Jerome KR, and Boeckh M
- Subjects
- Adult, Humans, Kidney pathology, Male, Middle Aged, Polymerase Chain Reaction, Time Factors, Blood Transfusion, Autologous, Heart Transplantation, Kidney virology, Polyomavirus genetics
- Abstract
Chronic renal dysfunction is common in non-renal solid organ (SOT) and hematopoietic stem cell transplant (HSCT) recipients and is commonly attributed to calcineurin inhibitor toxicity, often without renal histopathologic evaluation. Polyomavirus nephropathy (PVN) is an important cause of allograft dysfunction in kidney transplant recipients but has rarely been reported in native kidneys of non-renal transplant recipients. We report the clinical, pathologic and virologic features of PVN in native kidneys of two allograft recipients. In both, severe renal dysfunction was accompanied by histopathologic evidence of PVN, including characteristic viral inclusions by routine stains, immunohistochemistry and electron microscopy. High levels of BK virus (BKV) DNA were detected in kidney tissue of patients using BKV-specific polymerase chain reaction (PCR). In 1 patient, high levels of BKV DNA were detected in plasma and urine, and administration of low-dose cidofovir was associated with clearance of BK viremia. These results extend the populations in which PVN has been documented in native kidneys to include heart and stem cell transplant recipients, and suggest that cidofovir has activity against BKV in vivo. Studies to define the incidence and potential contribution of PVN to chronic renal dysfunction commonly attributed to calcineurin inhibitor toxicity in non-renal transplant recipients are warranted.
- Published
- 2005
- Full Text
- View/download PDF
48. Immune evasion proteins of human cytomegalovirus do not prevent a diverse CD8+ cytotoxic T-cell response in natural infection.
- Author
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Manley TJ, Luy L, Jones T, Boeckh M, Mutimer H, and Riddell SR
- Subjects
- Antigen Presentation, Antigens, Viral genetics, Antigens, Viral immunology, Cytomegalovirus genetics, Cytomegalovirus pathogenicity, Fibroblasts virology, Flow Cytometry, Genes, Immediate-Early, Histocompatibility Antigens Class I immunology, Humans, Mutation, Viral Proteins physiology, Cytomegalovirus immunology, Cytomegalovirus Infections immunology, T-Lymphocytes, Cytotoxic immunology, Viral Proteins immunology
- Abstract
Although cytomegalovirus (CMV) expresses proteins that interfere with antigen presentation by class I major histocompatibility complex (MHC) molecules, CD8+ cytotoxic T cells (CTLs) are indispensable for controlling infection and maintaining latency. Here, a cytokine flow cytometry assay that employs fibroblasts infected with a mutant strain of CMV (RV798), which is deleted of the 4 viral genes that are responsible for interfering with class I MHC presentation, was used to examine the frequency and specificity of the CD8+ CTLs to CMV in immunocompetent CMV-seropositive individuals. A large fraction of the CD8+ CTL response was found to be specific for viral antigens expressed during the immediate early and early phases of virus replication and presented by fibroblasts infected with RV798 but not wild-type CMV. These results demonstrate that the inhibition of class I antigen presentation observed in CMV-infected cells in vitro is not sufficient to prevent the induction of a broad repertoire of CD8+ CTLs after natural infection in vivo. Thus, reconstitution of T-cell immunity in immunodeficient patients by cell therapy or by vaccination may need to target multiple viral antigens to completely restore immunologic control of CMV.
- Published
- 2004
- Full Text
- View/download PDF
49. The impact of cytomegalovirus serostatus of donor and recipient before hematopoietic stem cell transplantation in the era of antiviral prophylaxis and preemptive therapy.
- Author
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Boeckh M and Nichols WG
- Subjects
- Cytomegalovirus Infections prevention & control, Humans, Antiviral Agents therapeutic use, Cytomegalovirus Infections drug therapy, Cytomegalovirus Infections mortality, Hematopoietic Stem Cell Transplantation mortality
- Abstract
In the current era of effective prophylactic and preemptive therapy, cytomegalovirus (CMV) is now a rare cause of early mortality after hematopoietic stem cell transplantation (HSCT). However, the ultimate goal of completely eliminating the impact of CMV on survival remains elusive. Although the direct effects of CMV (ie, CMV pneumonia) have been largely eliminated, several recent cohort studies show that CMV-seropositive transplant recipients and seronegative recipients of a positive graft appear to have a persistent mortality disadvantage when compared with seronegative recipients with a seronegative donor. Recipients of T-cell-depleted allografts and/or transplants from unrelated or HLA-mismatched donors seem to be predominantly affected. Reasons likely include both incomplete prevention of direct and indirect or immunomodulatory effects of CMV as well as consequences of drug toxicities. The effect of donor CMV serostatus on outcome remains controversial. Large multicenter cohort studies are needed to better define the subgroups of seropositive patients that may benefit from intensified prevention strategies and to define the impact of CMV donor serostatus in the era of high-resolution HLA matching. Prevention strategies may require targeting both the direct and indirect effects of CMV infection by immunologic or antiviral drug strategies.
- Published
- 2004
- Full Text
- View/download PDF
50. Cyclophosphamide metabolism is affected by azole antifungals.
- Author
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Marr KA, Leisenring W, Crippa F, Slattery JT, Corey L, Boeckh M, and McDonald GB
- Subjects
- Adolescent, Adult, Bone Marrow Transplantation, Drug Interactions, Humans, Antifungal Agents administration & dosage, Antineoplastic Agents, Alkylating pharmacokinetics, Candidiasis prevention & control, Cyclophosphamide pharmacokinetics, Fluconazole administration & dosage, Itraconazole administration & dosage
- Abstract
We performed a randomized trial to compare the safety and efficacy of itraconazole with fluconazole in preventing fungal infections in patients undergoing allogeneic stem cell transplantation (SCT). Itraconazole (intravenous 200 mg daily, or oral solution 2.5 mg/kg 3 times daily) and fluconazole (intravenous or oral, 400 mg daily) were administered with the start of conditioning therapy, until at least 120 days after SCT. After enrollment of the first 197 patients, a data and safety monitoring board reviewed potential drug-related toxicities. Patients who received itraconazole developed higher serum bilirubin and creatinine values in the first 20 days after SCT, with highest values in patients who received itraconazole concurrent with cyclophosphamide (CY) conditioning. Analysis of CY metabolism in a subset of patients demonstrated higher exposure to toxic metabolites among recipients of itraconazole compared with fluconazole. These data suggest that azole antifungals, through differential inhibition of hepatic cytochrome P-450 isoenzymes, affect CY metabolism and conditioning-related toxicities.
- Published
- 2004
- Full Text
- View/download PDF
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