Bio

Bio


Dr. Janice (Wes) Brown specializes in the treatment of infectious complications that occur in patients who are receiving cancer treatments or are undergoing transplantation of solid organs or hematopoietic cells. She has been a member of the Blood and Marrow Transplantation faculty for more than twenty years and co-founded the Immunocompromised Host Infectious Diseases consultation service. Dr. Brown?s special interest is to understand the nature of immunodeficiency resulting from an ever- evolving spectrum of targeted and immunomodulatory therapy. Her laboratory studies approaches to enhance and/or rebuild protective immunity. She is a leader in the design and execution of clinical trials of new treatments for infections that have significantly improved the outcomes of high-risk patients.

Clinical Focus


  • Cancer > Blood and Marrow Transplant
  • Blood and Marrow Transplantation
  • Blood and Marrow Transplantation / Infectious Diseases
  • Infectious Disease

Academic Appointments


Boards, Advisory Committees, Professional Organizations


  • Microbiology Laboratory Liason, Blood & Marrow Transplantation (1996 - 2009)
  • Organizer, H1N1 Influenza Multidisciplinary Team (2009 - Present)
  • Member, Hospital Design Team (2008 - 2010)
  • Member, Infection Control and Hospital Epidemiology (1996 - Present)

Professional Education


  • Board Certification: Infectious Disease, American Board of Internal Medicine (1994)
  • Fellowship:Stanford University School of Medicine Registrar (1993) CA
  • Residency:Stanford University School of Medicine Registrar (1990) CA
  • Internship:Stanford University School of Medicine Registrar (1988) CA
  • Medical Education:University Of Virginia (1987) VA
  • BA, Stanford University, Biological Sciences (1981)
  • MD, University of Virginia, Hypoxemic myocardial injury (1987)
  • Residency, Stanford University, Internal Medicine (1990)
  • Fellowship, Stanford University, Infectious Diseases (1996)

Research & Scholarship

Clinical Trials


  • Bone Marrow Grafting for Leukemia and Lymphoma Recruiting

    The purpose of this study is to obtain tissue samples for ongoing studies regarding transplant outcomes and complications.

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  • A Multicenter, Randomized, Double-Blind, Comparative Study to Evaluate the Safety, Tolerability, and Efficacy of 2 Dosing Regimens of an Antifungal Drug in the Treatment of Fungal Infections in Adults (0991-801)(COMPLETED) Not Recruiting

    Comparison of the safety and effectiveness of standard drug dosing versus a daily dose 3 times higher than the standard dose in patients with invasive candidiasis (bloodstream and/or systemic yeast infections)

    Stanford is currently not accepting patients for this trial.

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  • A Study of an Investigational V212/Heat-Treated Varicella-Zoster Virus (VZV) Vaccine in Immunocompromised Adults (V212-002) Not Recruiting

    This study will evaluate the safety and immunogenicity of a heat-treated VZV vaccine in autologous or allogeneic hematopoietic cell transplant (HCT) recipients, human immunodeficiency virus (HIV)-infected participants with a baseline cluster of differentiation 4 (CD4) cell count ?200 cells/mm^3, participants with solid tumor malignancy (STM; breast, colorectal, lung, or ovarian malignancies) receiving chemotherapy, and participants with hematologic malignancy (HM; leukemia or leukemia-like disease, lymphoma or lymphoma-like disease, or multiple myeloma). The primary hypothesis is that the heat-treated VZV vaccine will elicit significant VZV-specific immune responses measured by either glycoprotein-based enzyme-linked immunosorbent assay (gpELISA) or VZV gamma interferon enzyme-linked immunospot (IFN-ELISPOT) at 28 days post dose vaccination 4 in, HIV-infected participants, participants with STM, and participants with HM. The primary immunogenicity objective and endpoints were considered by the protocol as exploratory for the autologous and allogeneic HCT groups.

    Stanford is currently not accepting patients for this trial. For more information, please contact Dora Ho, (650) 736 - 2442.

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  • A Study to Evaluate a Therapeutic Vaccine, ASP0113, in Cytomegalovirus (CMV)-Seropositive Recipients Undergoing Allogeneic, Hematopoietic Cell Transplant (HCT) Not Recruiting

    The purpose of the study was to evaluate the efficacy of ASP0113 compared with placebo as measured by a primary composite endpoint of overall mortality and CMV end organ disease (EOD) through 1 year post-transplant. Safety of ASP0113 in participants undergoing allogeneic HCT will also be evaluated.

    Stanford is currently not accepting patients for this trial. For more information, please contact Physician Referrals, 650-723-0822.

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  • A Study to Evaluate the Safety and Efficacy of Inactivated Varicella-zoster Vaccine (VZV) as a Preventative Treatment for Herpes Zoster (HZ) and HZ-related Complications in Adult Participants With Solid Tumor or Hematologic Malignancy (V212-011) Not Recruiting

    This is a randomized, double-blind, placebo-controlled study to assess the safety and tolerability of V212 when administered to adults with solid tumor malignancy (STM) receiving chemotherapy and to assess the impact of V212 on the development of herpes zoster (HZ) in adults with STM receiving chemotherapy. The primary hypothesis is that vaccination with V212 will reduce the incidence of HZ compared with placebo in adults with STM (lower bound of the 97.5% {one-sided ?=0.0125} confidence interval [CI] for the estimated vaccine efficacy in adults with STM be >25%). Participants with hematologic malignancy (HM) were also enrolled and were to be originally included in the primary and secondary objectives and analyses. After an interim analysis demonstrated clear evidence of futility of V212 in the HM population, enrollment of this population was stopped and all HM-related objectives and analyses were made exploratory and are not reported in this record.

    Stanford is currently not accepting patients for this trial. For more information, please contact Sumana Shashidhar, (650) 736 - 0828.

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  • A Study to Evaluate the Safety and Efficacy of Inactivated Varicella-zoster Vaccine (VZV) as a Preventative Treatment for Herpes Zoster (HZ) and HZ-related Complications in Participants Undergoing Hematopoietic Cell Transplants (HCTs) (V212-001) Not Recruiting

    This is a randomized, double-blind, placebo-controlled study to assess the safety and efficacy of inactivated VZV vaccine for the prevention of HZ and HZ-related complications in adult recipients of autologous hematopoietic cell transplants (HCTs). The primary hypothesis is that vaccination with V212 vaccine will reduce the incidence of herpes zoster (HZ) compared to placebo when administered to recipients of HCT. The statistical criterion for success requires that the lower bound of the 95% confidence interval for the estimated vaccine efficacy in the V212 recipients (excluding the high-antigen lot) compared with that in the placebo recipients is >25%.

    Stanford is currently not accepting patients for this trial. For more information, please contact Janice Smith-Williams, (650) 724 - 4155.

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  • An Observational Study of Fungal Biomarkers (MK-0000-089) Not Recruiting

    The purpose of this study is to evaluate the relationship between fungal biomarker levels during anti-fungal therapy and the success of treatment for fungal infection. The primary hypothesis is that over the initial two weeks of anti-fungal therapy, fungal biomarkers from participants with invasive aspergillosis (IA) will be lower for those with a successful clinical outcome compared to those with a failed clinical outcome.

    Stanford is currently not accepting patients for this trial. For more information, please contact Janice Smith-Williams, (650) 724 - 4155.

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  • Isavuconazole (BAL8557) for Primary Treatment of Invasive Aspergillosis Not Recruiting

    The purpose of this study is to compare the efficacy and safety of isavuconazole versus voriconazole in the treatment of patients with invasive aspergillosis.

    Stanford is currently not accepting patients for this trial. For more information, please contact Janice Smith-Williams, (650) 724 - 4155.

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  • Isavuconazole (BAL8557) in the Treatment of Candidemia and Other Invasive Candida Infections Not Recruiting

    The purpose of the study is to compare the safety and efficacy of isavuconazole versus caspofungin followed by voriconazole in the treatment of candidemia and other invasive Candida infections.

    Stanford is currently not accepting patients for this trial. For more information, please contact Physician Referrals, 650-723-0822.

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  • Isavuconazole in the Treatment of Renally Impaired Aspergillosis and Rare Fungi Not Recruiting

    The purpose of this study is to investigate the efficacy and safety of isavuconazole in the treatment of renally impaired participants with invasive fungal infections caused by Aspergillus and participants with invasive fungal disease caused by rare fungi.

    Stanford is currently not accepting patients for this trial. For more information, please contact Sumana Shashidhar, (650) 498-1981.

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  • Oral Triple Combination Antiviral Drug Therapy for Treatment of Influenza A in Immunocompromised Subjects Not Recruiting

    This Phase 2, open label, randomized study will investigate the virologic benefit, clinical efficacy, safety, and tolerability of amantadine and ribavirin with oseltamivir (TCAD) versus oseltamivir monotherapy for the treatment of all strains of influenza A in immunocompromised adult and pediatric subjects.

    Stanford is currently not accepting patients for this trial. For more information, please contact Joanna Schaenman, (650) 387 - 0127.

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  • Post T-plant Infusion of Allogeneic Cytokine Induced Killer (CIK) Cells as Consolidative Therapy in Myelodysplastic Syndromes/Myeloproliferative Disorders Not Recruiting

    Allogeneic stem cell transplantation (transplant of blood cells from another individual) is a treatment option for patients with myelodysplasia or myeloproliferative Disorders. During the course of this study, it will be evaluated whether a particular type of blood cell, called a cytokine-induced killer (CIK) cell, may add benefit to allogeneic stem cell transplantation. CIK cells are present in small quantities in the bloodstream but their numbers can be expanded after a brief period of nurturing in a laboratory.

    Stanford is currently not accepting patients for this trial. For more information, please contact Physician Referrals, 650-723-0822.

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  • Prophylactic Use of Maribavir for the Prevention of Cytomegalovirus (CMV) Disease in Stem Cell Transplant Recipients Not Recruiting

    The purpose of this research study is to investigate whether or not maribavir is safe and effective for preventing CMV disease when taken by mouth for up to 12 weeks in patients who have had a stem cell transplant.

    Stanford is currently not accepting patients for this trial. For more information, please contact Janice Brown, (650) 723 - 0822.

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  • Safety and Efficacy Study of a New Antiviral Drug to Prevent Cytomegalovirus Reactivation in Bone Marrow Transplanted Patients Not Recruiting

    The aim of the study is to find out whether AIC246 is safe and efficacious in lowering the chances of the cytomegalovirus becoming active again and causing illness after an HBPC transplant (allogeneic stem cell transplant).

    Stanford is currently not accepting patients for this trial. For more information, please contact Joanna Schaenman, (650) 387 - 0127.

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Teaching

2019-20 Courses


Graduate and Fellowship Programs


Publications

All Publications


  • Inactivated varicella zoster vaccine in autologous haemopoietic stem-cell transplant recipients: an international, multicentre, randomised, double-blind, placebo-controlled trial LANCET Winston, D. J., Mullane, K. M., Cornely, O. A., Boeckh, M. J., Brown, J., Pergam, S. A., Trociukas, I., Zak, P., Craig, M. D., Papanicolaou, G. A., Velez, J. D., Panse, J., Hurtado, K., Fernsler, D. A., Stek, J. E., Pang, L., Su, S., Zhao, Y., Chan, I. F., Kaplan, S. S., Parrino, J., Lee, I., Popmihajlov, Z., Annunziato, P. W., Arvin, A., V212 Protocol 001 Trial Team 2018; 391 (10135): 2116?27

    Abstract

    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.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).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 24 years (SD 13) in the vaccine consistency lot group and 23 years (SD 13) in the placebo group. 42 (8%) of 538 participants in the vaccine consistency lot group (329 per 1000 person-years) and 113 (21%) of 535 in the placebo group (919 per 1000 person-years) had a confirmed case of herpes zoster. The estimated vaccine efficacy was 638% (95% CI 484-746), 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 02%, 95% CI -51 to 55) and serious vaccine-related adverse events (five [1%] vs five [1%]; risk difference 01%, -14 to 11) 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 226%, 95% CI 185-266; p<00001).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.Merck & Co., Inc.

    View details for PubMedID 29856344

  • Echinocandin prophylaxis in patients undergoing haematopoietic cell transplantation and other treatments for haematological malignancies. The Journal of antimicrobial chemotherapy Epstein, D. J., Seo, S. K., Brown, J. M., Papanicolaou, G. A. 2018; 73 (suppl_1): i60?i72

    Abstract

    Antifungal prophylaxis is the standard of care for patients undergoing intensive chemotherapy for haematological malignancy or haematopoietic cell transplantation (HCT). Prophylaxis with azoles reduces invasive fungal infections and may reduce mortality. However, breakthrough infections still occur, and the use of azoles is sometimes complicated by pharmacokinetic variability, drug interactions, adverse events and other issues. Echinocandins are highly active against Candida species, including some organisms resistant to azoles, and have some clinical activity against Aspergillus species as well. Although currently approved echinocandins require daily intravenous administration, the drugs have a favourable safety profile and more predictable pharmacokinetics than mould-active azoles. Clinical data support the efficacy and safety of echinocandins for antifungal prophylaxis in haematology and HCT patients, though data are less robust than for azoles. Notably, sparse evidence exists supporting the use of echinocandins as antifungal prophylaxis for patients with significant graft-versus-host disease (GvHD) after HCT. Two drugs that target (1,3)-?-d-glucan are in development, including an oral glucan synthase inhibitor and an echinocandin with unique pharmacokinetics permitting subcutaneous and weekly administration. Echinocandins are a reasonable alternative to azoles and other agents for antifungal prophylaxis in patients undergoing intensive chemotherapy for haematological malignancy or those receiving HCT, excluding those with significant GvHD.

    View details for PubMedID 29304213

  • Letermovir Prophylaxis for Cytomegalovirus in Hematopoietic-Cell Transplantation NEW ENGLAND JOURNAL OF MEDICINE Marty, F. M., Ljungman, P., Chemaly, R. F., Maertens, J., Dadwal, S. S., Duarte, R. F., Haider, S., Ullmann, A. J., Katayama, Y., Brown, J., Mullane, K. M., Boeckh, M., Blumberg, E. A., Einsele, H., Snydman, D. R., Kanda, Y., DiNubile, M. J., Teal, V. L., Wan, H., Murata, Y., Kartsonis, N. A., Leavitt, R. Y., Badshah, C. 2017; 377 (25): 2433?44

    Abstract

    Cytomegalovirus (CMV) infection remains a common complication after allogeneic hematopoietic-cell transplantation. Letermovir is an antiviral drug that inhibits the CMV-terminase complex.In this phase 3, double-blind trial, we randomly assigned CMV-seropositive transplant recipients, 18 years of age or older, in a 2:1 ratio to receive letermovir or placebo, administered orally or intravenously, through week 14 after transplantation; randomization was stratified according to trial site and CMV disease risk. Letermovir was administered at a dose of 480 mg per day (or 240 mg per day in patients taking cyclosporine). Patients in whom clinically significant CMV infection (CMV disease or CMV viremia leading to preemptive treatment) developed discontinued the trial regimen and received anti-CMV treatment. The primary end point was the proportion of patients, among patients without detectable CMV DNA at randomization, who had clinically significant CMV infection through week 24 after transplantation. Patients who discontinued the trial or had missing end-point data at week 24 were imputed as having a primary end-point event. Patients were followed through week 48 after transplantation.From June 2014 to March 2016, a total of 565 patients underwent randomization and received letermovir or placebo beginning a median of 9 days after transplantation. Among 495 patients with undetectable CMV DNA at randomization, fewer patients in the letermovir group than in the placebo group had clinically significant CMV infection or were imputed as having a primary end-point event by week 24 after transplantation (122 of 325 patients [37.5%] vs. 103 of 170 [60.6%], P<0.001). The frequency and severity of adverse events were similar in the two groups overall. Vomiting was reported in 18.5% of the patients who received letermovir and in 13.5% of those who received placebo; edema in 14.5% and 9.4%, respectively; and atrial fibrillation or flutter in 4.6% and 1.0%, respectively. The rates of myelotoxic and nephrotoxic events were similar in the letermovir group and the placebo group. All-cause mortality at week 48 after transplantation was 20.9% among letermovir recipients and 25.5% among placebo recipients.Letermovir prophylaxis resulted in a significantly lower risk of clinically significant CMV infection than placebo. Adverse events with letermovir were mainly of low grade. (Funded by Merck; ClinicalTrials.gov number, NCT02137772 ; EudraCT number, 2013-003831-31 .).

    View details for PubMedID 29211658

  • Cryopreserved Ex Vivo-Expanded Allogeneic Myeloid Progenitor Cell Product Protects Neutropenic Mice From a Lethal Fungal Infection CELL TRANSPLANTATION Domen, J., Christensen, J. L., Gille, D., Smith-Berdan, S., Fong, T., Brown, J. Y., Sedello, A. K. 2016; 25 (1): 17?33

    Abstract

    Severe neutropenia induced by chemotherapy or conditioning for hematopoietic cell transplantation often results in morbidity and mortality due to infection by opportunistic pathogens. A system has been developed to generate ex vivo-expanded mouse myeloid progenitor cells (mMPCs) that produce functional neutrophils in vivo upon transplantation in a pathogen challenge model. It has previously been demonstrated that transplantation of large numbers of freshly isolated myeloid progenitors from a single donor provides survival benefit in radiation-induced neutropenic mice. In the present work, an ex vivo-expanded and cryopreserved mMPC product generated from an allogeneic donor pool retains protective activity in vivo in a lethal fungal infection model. Infusion of the allogeneic pooled mMPC product is effective in preventing death from invasive Aspergillus fumigatus in neutropenic animals, and protection is dose dependent. Cell progeny from the mMPC product is detected in the bone marrow, spleen, blood, and liver by flow cytometry 1 week postinfusion but is no longer evident in most animals 4 weeks posttransplant. In this model, the ex vivo-generated pooled allogeneic mMPC product (i) expands and differentiates in vivo; (ii) is functional and prevents death from invasive fungal infection; and (iii) does not permanently engraft or cause allosensitization. These data suggest that an analogous ex vivo-expanded human myeloid progenitor cell product may be an effective off-the-shelf bridging therapy for the infectious complications that develop during hematopoietic recovery following hematopoietic cell transplantation or intensive chemotherapy.

    View details for DOI 10.3727/096368915X687688

    View details for Web of Science ID 000369557000002

    View details for PubMedID 25812169

  • Peritoneal Coccidioidomycosis: a Rare Case Report and Review of the Literature JOURNAL OF GASTROINTESTINAL AND LIVER DISEASES Storage, T. R., Segal, J., Brown, J. 2015; 24 (4): 527-530

    Abstract

    Coccidioidomycosis is a fungal infection endemic to the southwestern United States that typically causes a self-limited pulmonary illness. Extrapulmonary dissemination is extremely rare and typically localized to the skin, bone, and meninges. The gastrointestinal system has generally been thought to be spared from this disease. This report describes a patient who was initially diagnosed with pulmonary coccidioidomycosis with mediastinal lymphadenopathy and skin dissemination. Ten months after completion of treatment, he presented with nonspecific abdominal pain and diffuse musculoskeletal and constitutional symptoms. Radiographic imaging revealed near resolution of previously noted thoracic findings but new peritoneal thickening and enhancement suggestive of peritoneal carcinomatosis. Laparoscopic biopsies confirmed Coccidioides immitis by culture and histology without evidence of other abnormalities. This case is unique for several reasons. It is one of a relatively small number of cases that describes a diagnosis of peritoneal coccidioidomycosis and the first case identified in which a healthy patient developed extensive peritoneal disease in spite of near-complete resolution of pulmonary and skin manifestations after appropriate treatment. This case underscores the complexity of this disease and motivates more investigation into pathophysiology and treatment considerations of coccidioidomycosis in the gastrointestinal system. We will review the risk factors associated with dissemination, the interpretation of serologies, the characteristics of patients with peritoneal involvement, and finally, the current treatment guidelines.

    View details for Web of Science ID 000367491500020

  • Gastrointestinal Mucormycosis Initially Manifest as Hematochezia from Arterio-Enteric Fistula DIGESTIVE DISEASES AND SCIENCES Cloyd, J. M., Brown, J., Sinclair, T., Jenks, D., Desai, J., Longacre, T., Chandra, V., Shelton, A. 2014; 59 (12): 2905-2908
  • Letermovir for Cytomegalovirus Prophylaxis in Hematopoietic-Cell Transplantation NEW ENGLAND JOURNAL OF MEDICINE Chemaly, R. F., Ullmann, A. J., Stoelben, S., Richard, M., Bornhaeuser, M., Groth, C., Einsele, H., Silverman, M., Mullane, K. M., Brown, J., Nowak, H., Koelling, K., Stobernack, H. P., Lischka, P., Zimmermann, H., Ruebsamen-Schaeff, H., Champlin, R. E., Ehninger, G., AIC246 Study Team 2014; 370 (19): 1781?89

    Abstract

    Cytomegalovirus (CMV) infection is a leading cause of illness and death in patients who have undergone allogeneic hematopoietic-cell transplantation. Available treatments are restricted by clinically significant toxic effects and drug resistance.In this phase 2 study, we evaluated the effect of letermovir (also known as AIC246), a new anti-CMV drug with a novel mechanism of action, on the incidence and time to onset of prophylaxis failure in CMV-seropositive recipients of allogeneic hematopoietic-cell transplants from matched related or unrelated donors. From March 2010 through October 2011, we randomly assigned 131 transplant recipients in a 3:1 ratio to three sequential study cohorts according to a double-blind design. Patients received oral letermovir (at a dose of 60, 120, or 240 mg per day, or matching placebo) for 12 weeks after engraftment. The primary end point was all-cause prophylaxis failure, defined as discontinuation of the study drug because of CMV antigen or DNA detection, end-organ disease, or any other cause. Patients underwent weekly surveillance for CMV infection.The reduction in the incidence of all-cause prophylaxis failure was dose-dependent. The incidence of prophylaxis failure with letermovir, as compared with placebo, was 48% versus 64% at a daily letermovir dose of 60 mg (P=0.32), 32% at a dose of 120 mg (P=0.01), and 29% at a dose of 240 mg (P=0.007). Kaplan-Meier time-to-onset profiles for prophylaxis failure showed a significant difference in the comparison of letermovir at a dose of 240 mg per day with placebo (P=0.002). The safety profile of letermovir was similar to placebo, with no indication of hematologic toxicity or nephrotoxicity.Letermovir, as compared with placebo, was effective in reducing the incidence of CMV infection in recipients of allogeneic hematopoietic-cell transplants. The highest dose (240 mg per day) had the greatest anti-CMV activity, with an acceptable safety profile. (Funded by AiCuris; ClinicalTrials.gov number, NCT01063829.).

    View details for PubMedID 24806159

  • Comparative cost-effectiveness analysis of voriconazole and fluconazole for prevention of invasive fungal infection in patients receiving allogeneic hematopoietic cell transplants AMERICAN JOURNAL OF HEALTH-SYSTEM PHARMACY Mauskopf, J., Chirila, C., Graham, J., Gersten, I. D., Leather, H., Maziarz, R. T., Baden, L. R., Bolanos-Meade, J., Brown, J. Y., Walsh, T. J., Horowitz, M. H., Kurtzberg, J., Marr, K. A., Wingard, J. R. 2013; 70 (17): 1518?27

    Abstract

    The cost-effectiveness of voriconazole versus fluconazole prophylaxis against fungal infections in hematopoietic cell transplant (HCT) recipients is investigated.A decision-analytic model was developed to estimate the drug costs associated with planned or supplemental prophylaxis and empirical therapy and the costs of treating suspected or documented invasive fungal infections (IFIs) in HCT recipients. Published clinical trial data on 599 patients who received 100-180 days of prophylactic therapy with voriconazole or fluconazole were used to model specified IFI-prevention and mortality outcomes; 6-month, 12-month, and lifetime incremental cost-effectiveness ratios (ICERs) were estimated, with a bootstrap analysis performed to reffect the uncertainty of the clinical trial data.Estimated mean total prophylaxis and IFI-related costs associated with voriconazole versus fluconazole prophylaxis over 12 months were higher in the entire study population and among patients receiving HCT for diagnoses other than acute myeloid leukemia (AML) but were not significantly different for patients with AML. The cost per IFI avoided ($66,919) and the cost per life-year gained ($5,453) were lower among patients with AML who received voriconazole relative to the full study population. ICERs were more favorable for voriconazole over a 6-month time frame and when modeling was conducted using generic price data. Assuming a threshold value of $50,000 for one year of life gained, the calculated probability of voriconazole being cost-effective was 33% for the full study population and 85% for the AML subgroup.The decision model indicated that voriconazole prophylaxis was cost-effective for patients undergoing allogeneic HCT for AML.

    View details for DOI 10.2146/ajhp120599

    View details for Web of Science ID 000323803800015

    View details for PubMedID 23943184

    View details for PubMedCentralID PMC4019750

  • Successful Surgical and Medical Treatment of Rhizopus Osteomyelitis Following Hematopoietic Cell Transplantation ORTHOPEDICS Vashi, N., Avedian, R., Brown, J., Arai, S. 2012; 35 (10): E1556-E1561

    Abstract

    Mucormycosis has been reported in otherwise healthy individuals; however, it is primarily seen in immunocompromised patients, such as those with diabetes mellitus, malignancy, or chronic graft-versus-host disease, and has a high mortality rate. Because most cases of mucormycosis are associated with contiguous rhinocerebral infection, only 5 cases of isolated musculoskeletal Rhizopus infection have been reported in the literature. One patient underwent hematopoietic cell transplant, which resulted in a fatal outcome.This article describes the successful treatment of isolated Rhizopus osteomyelitis in a patient who underwent hematopoietic cell transplant using a combined surgical and medical approach. A 33-year-old woman with pre-B cell acute lymphoblastic leukemia underwent hematopoietic cell transplant with few complications but developed chronic graft-versus-host disease 8 months posttransplant. She was treated with high-dose steroids for 6 weeks before she was admitted for severe right tibial pain in the absence of trauma. Early detection, aggressive therapies, and a multidisciplinary surgical and medical team allowed for the microbiologically confirmed resolution of the infection. Treatment included multiagent antimicrobial therapy with amphotericin B, daptomycin, and ertapenem. Several surgical irrigation and debridement procedures were also performed, with the eventual placement of amphotericin-impregnated polymethylmethacrylate cement beads and small fragment titanium screws. The patient continued taking postoperative antifungal treatment for 7 months after discharge. Six months following the discontinuation of antifungal therapy, the team's multidisciplinary approach achieved a continued resolution of the patient's infection and a return to a fully ambulatory and radiographically proven recovery without limb loss.

    View details for DOI 10.3928/01477447-20120919-30

    View details for Web of Science ID 000309814600019

    View details for PubMedID 23027498

  • Prophylactic rituximab after allogeneic transplantation decreases B-cell alloimmunity with low chronic GVHD incidence BLOOD Arai, S., Sahaf, B., Narasimhan, B., Chen, G. L., Jones, C. D., Lowsky, R., Shizuru, J. A., Johnston, L. J., Laport, G. G., Weng, W., Benjamin, J. E., Schaenman, J., Brown, J., Ramirez, J., Zehnder, J. L., Negrin, R. S., Miklos, D. B. 2012; 119 (25): 6145-6154

    Abstract

    B cells are involved in the pathogenesis of chronic GVHD (cGVHD). We hypothesized that prophylactic anti-B-cell therapy delivered 2 months after transplantation would decrease allogeneic donor B-cell immunity and possibly the incidence of cGVHD. Therefore, in the present study, patients with high-risk chronic lymphocytic leukemia (n = 22) and mantle-cell lymphoma (n = 13) received a total lymphoid irradiation of 80 cGy for 10 days and antithymocyte globulin 1.5 mg/kg/d for 5 days. Rituximab (375 mg/m(2)) was infused weekly on days 56, 63, 70, and 77 after transplantation. The incidence of acute GVHD was 6%. The cumulative incidence of cGVHD was 20%. Nonrelapse mortality was 3%. Rituximab treatment after allogeneic transplantation significantly reduced B-cell allogeneic immunity, with complete prevention of alloreactive H-Y Ab development in male patients with female donors (P = .01). Overall survival and freedom from progression at 4 years for chronic lymphocytic leukemia patients were 73% and 47%, respectively; for mantle-cell lymphoma patients, they were 69% and 53%, respectively.

    View details for DOI 10.1182/blood-2011-12-395970

    View details for PubMedID 22563089

  • Co-transplantation of pure blood stem cells with antigen-specific but not bulk T cells augments functional immunity PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Mueller, A. M., Shashidhar, S., Kuepper, N. J., Kohrt, H. E., Florek, M., Negrin, R. S., Brown, J. M., Shizuru, J. A. 2012; 109 (15): 5820-5825

    Abstract

    Impaired immunity is a fundamental obstacle to successful allogeneic hematopoietic cell transplantation. Mature graft T cells are thought to provide protection from infections early after transplantation, but can cause life-threatening graft-vs.-host disease. Human CMV is a major pathogen after transplantation. We studied reactivity against the mouse homologue, murine CMV (MCMV), in lethally irradiated mice given allogeneic purified hematopoietic stem cells (HSCs) or HSCs supplemented with T cells or T-cell subsets. Unexpectedly, recipients of purified HSCs mounted superior antiviral responses compared with recipients of HSC plus unselected bulk T cells. Furthermore, supplementation of purified HSC grafts with CD8(+) memory or MCMV-specific T cells resulted in enhanced antiviral reactivity. Posttransplantation lymphopenia promoted massive expansion of MCMV-specific T cells when no competing donor T cells were present. In recipients of pure HSCs, naive and memory T cells and innate lymphoid cell populations developed. In contrast, the lymphoid pool in recipients of bulk T cells was dominated by effector memory cells. These studies show that pure HSC transplantations allow superior protective immunity against a viral pathogen compared with unselected mature T cells. This reductionist transplant model reveals the impact of graft composition on regeneration of host, newly generated, and mature transferred T cells, and underscores the deleterious effects of bulk donor T cells. Our findings lead us to conclude that grafts composed of purified HSCs provide an optimal platform for in vivo expansion of selected antigen-specific cells while allowing the reconstitution of a naive T-cell pool.

    View details for DOI 10.1073/pnas.1120237109

    View details for PubMedID 22440752

  • Sirolimus and mycophenolate mofetil as GVHD prophylaxis in myeloablative, matched-related donor hematopoietic cell transplantation BONE MARROW TRANSPLANTATION Johnston, L., Florek, M., Armstrong, R., McCune, J. S., Arai, S., Brown, J., Laport, G., Lowsky, R., Miklos, D., Shizuru, J., Sheehan, K., Lavori, P., Negrin, R. 2012; 47 (4): 581-588

    Abstract

    We investigated sirolimus and mycophenolate mofetil (MMF) as GVHD prophylaxis in patients with advanced hematological malignancies receiving myeloablative hematopoietic cell transplantation (HCT) from HLA-identical sibling donors. On the basis of pre-study stopping rules, the trial was closed to accrual after enrollment of 11 adult patients. In all, 7 of the 11 patients received BU-containing preparative regimens. Sirolimus was discontinued in three patients because of the toxicity-related events of severe sinusoidal obstructive syndrome, portal vein thrombosis, altered mental status and in one patient because of the risk of poor wound healing. In all, 6 of the 11 patients developed grade II-IV acute GVHD (AGVHD) a median of 15.5 days post HCT. Two of three patients with grade IV AGVHD had sirolimus discontinued by 9 days post HCT. All patients responded to AGVHD therapy without GVHD-related deaths. There were two non-relapse- and two relapse-related deaths. At a median follow-up of 38 months (2-47 months), 7 of 11 patients were alive without disease. MMF and sirolimus GVHD prophylaxis did not reduce the risk of AGVHD, however, there were no GVHD-related deaths. The severe toxicities in the patients receiving the BU-containing preparative regimens limited the continued use of sirolimus and MMF for the prevention of AGVHD.

    View details for DOI 10.1038/bmt.2011.104

    View details for Web of Science ID 000302576700018

    View details for PubMedID 21552302

    View details for PubMedCentralID PMC3163055

  • Invasive Non-Aspergillus Mold Infections in Transplant Recipients, United States, 2001-2006 EMERGING INFECTIOUS DISEASES Park, B. J., Pappas, P. G., Wannemuehler, K. A., Alexander, B. D., Anaissie, E. J., Andes, D. R., Baddley, J. W., Brown, J. M., Brumble, L. M., Freifeld, A. G., Hadley, S., Herwaldt, L., Ito, J. I., Kauffman, C. A., Lyon, G. M., Marr, K. A., Morrison, V. A., Papanicolaou, G., Patterson, T. F., Perl, T. M., Schuster, M. G., Walker, R., Wingard, J. R., Walsh, T. J., Kontoyiannis, D. P. 2011; 17 (10): 1855-1864

    Abstract

    Recent reports describe increasing incidence of non-Aspergillus mold infections in hematopoietic cell transplant (HCT) and solid organ transplant (SOT) recipients. To investigate the epidemiology of infections with Mucorales, Fusarium spp., and Scedosporium spp. molds, we analyzed data from the Transplant-Associated Infection Surveillance Network, 23 transplant centers that conducted prospective surveillance for invasive fungal infections during 2001-2006. We identified 169 infections (105 Mucorales, 37 Fusarium spp., and 27 Scedosporium spp.) in 169 patients; 124 (73.4%) were in HCT recipients, and 45 (26.6%) were in SOT recipients. The crude 90-day mortality rate was 56.6%. The 12-month mucormycosis cumulative incidence was 0.29% for HCT and 0.07% for SOT. Mucormycosis incidence among HCT recipients varied widely, from 0.08% to 0.69%, with higher incidence in cohorts receiving transplants during 2003 and 2004. Non-Aspergillus mold infections continue to be associated with high mortality rates. The incidence of mucormycosis in HCT recipients increased substantially during the surveillance period.

    View details for DOI 10.3201/eid1710.110087

    View details for Web of Science ID 000295897300009

    View details for PubMedID 22000355

    View details for PubMedCentralID PMC3311117

  • Early CMV Viremia Is Associated with Impaired Viral Control following Nonmyeloablative Hematopoietic Cell Transplantation with a Total Lymphoid Irradiation and Antithymocyte Globulin Preparative Regimen BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION Schaenman, J. M., Shashidhar, S., Rhee, C., Wong, J., Navato, S., Wong, R. M., Ho, D. Y., Arai, S., Johnston, L., Brown, J. M. 2011; 17 (5): 693-702

    Abstract

    The reconstitution of immune function after hematopoietic cell transplant (HCT) plays an important role in the control of viral infections. Both donor and recipient cytomegalovirus (CMV) serostatus has been shown to contribute to effective immune function; however, the influence of a nonmyeloablative preparative (NMA) regimen using total lymphoid irradiation (TLI) and antithymocyte globulin (ATG) on antiviral immune reconstitution has not yet been described. In 117 recipients of NMA HCT patients following ATG and TLI, not unexpectedly, CMV viremia was seen in approximately 60% of the seropositive patients regardless of donor serostatus, and recipient seropositivity significantly increased the odds of CMV viremia after transplant in a multivariate analysis. The administration of ATG and TLI resulted in a strikingly earlier viremia in the posttransplant period when compared to the previously reported timing of viremia following myeloablative preparative regimens, especially for transplant recipients who were seropositive for CMV with seronegative donors. Furthermore, early viremia in the setting of a CMV nave donor was associated with a delay in functional antiviral control. These observations demonstrate the dynamic nature of immunity in relation to CMV antigen exposure in the complex environment resulting from NMA conditions where both donor and residual recipient immune response affect viral control.

    View details for DOI 10.1016/j.bbmt.2010.08.010

    View details for Web of Science ID 000290061500012

    View details for PubMedID 20736077

  • Long-term outcomes in patients with high-risk myeloid malignancies following matched related donor hematopoietic cell transplantation with myeloablative conditioning of BU, etoposide and CY BONE MARROW TRANSPLANTATION Naik, S., Wong, R., Arai, S., Brown, J., Laport, G., Lowsky, R., Miklos, D., Shizuru, J., Blume, K., Negrin, R., Johnston, L. 2011; 46 (2): 192-199

    Abstract

    Patients with high-risk or advanced myeloid malignancies have limited effective treatment options. These include high-dose therapy followed by allogeneic hematopoietic cell transplantation (HCT). We report a single-institution, long-term follow-up of 96 patients, median age 50 (range, 20-60) years, who received HLA-matched related HCT between 1992 and 2007. All patients were treated with a uniform preparatory regimen intended to enhance the widely used regimen of BU and CY that included: BU 16.0?mg/kg (days -8 to -5), etoposide 60?mg/kg (day -4), CY 60?mg/kg (day -2) with GVHD prophylaxis of CsA or FK506 and prednisone. Disease status at transplantation was high-risk AML (n=41), CML in second chronic phase or blast crisis (n=8), myelofibrosis and myeloproliferative disorders (n=8), and myelodysplasia (n=39). Thirty-six percent (n=35) of patients received BM whereas 64% (n=61) received G-CSF-mobilized PBPC. With a median follow-up of 5.6 years (range, 1.6-14.6 years) actuarial 5-year OS was 32% (95% CI 22-42) and 5-year EFS was 31% (95% CI 21-41). Relapse rate was 24% (95% CI 15-33) at 2 and 5 years. Nonrelapse mortality was 29% (95% CI 20-38) at day 100 and 38% (95% CI 29-47) at 1 year. Cumulative incidence of acute (grade II-IV) and extensive chronic GVHD was 27% (95% CI 18-36) and 29% (95% CI 18-40), respectively. There was no statistically significant difference in OS (31 vs 32%, P=0.89) or relapse rates (17 vs 28%, P=0.22) for recipients of BM vs PBPC, respectively. These results confirm that patients with high-risk or advanced myeloid malignancies can achieve long-term survival following myeloablative allogeneic HCT with aggressive conditioning.

    View details for DOI 10.1038/bmt.2010.114

    View details for PubMedID 20498648

  • Treatment of Acyclovir-Resistant Herpes Simplex Virus with Continuous Infusion of High-Dose Acyclovir in Hematopoietic Cell Transplant Patients BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION Kim, J. H., Schaenman, J. M., Ho, D. Y., Brown, J. M. 2011; 17 (2): 259-264

    Abstract

    Infection because of herpes simplex virus (HSV) that is resistant to acyclovir (ACV) poses treatment challenges in hematopoietic cell transplant (HCT) patients. We present a series of patients with ACV-resistant HSV following HCT who were successfully treated with continuous infusion high-dose ACV after failing standard treatment regimens for ACV-resistant HSV.

    View details for DOI 10.1016/j.bbmt.2010.06.020

    View details for Web of Science ID 000287350400010

    View details for PubMedID 20615475

  • Combined Effects of Interleukin-7 and Stem Cell Factor Administration on Lymphopoiesis after Murine Bone Marrow Transplantation BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION Chung, B., Min, D., Joo, L. W., Krampf, M. R., Huang, J., Yang, Y., Shashidhar, S., Brown, J., Dudl, E. P., Weinberg, K. I. 2011; 17 (1): 48-60

    Abstract

    The decreased ability of the thymus to generate T cells after bone marrow transplantation (BMT) is a clinically significant problem. Interleukin (IL)-7 and stem cell factor (SCF) induce proliferation, differentiation, and survival of thymocytes. Although previous studies have shown that administration of recombinant human IL-7 (rhIL-7) after murine and human BMT improves thymopoiesis and immune function, whether administration of SCF exerts similar effects is unclear. To evaluate independent or combinatorial effects of IL-7 and SCF in post-BMT thymopoiesis, bone marrow (BM)-derived mesenchymal stem cells transduced ex vivo with the rhIL-7 or murine SCF (mSCF) genes were cotransplanted with T cell-depleted BM cells into lethally irradiated mice. Although rhIL-7 and mSCF each improved immune reconstitution, the combination treatment had a significantly greater effect than either cytokine alone. Moreover, the combination treatment significantly increased donor-derived common lymphoid progenitors (CLPs) in BM, suggesting that transplanted CLPs expand more rapidly in response to IL-7 and SCF and may promote immune reconstitution. Our findings demonstrate that IL-7 and SCF might be therapeutically useful for enhancing de novo T cell development. Furthermore, combination therapy may allow the administration of lower doses of IL-7, thereby decreasing the likelihood of IL-7-mediated expansion of mature T cells.

    View details for DOI 10.1016/j.bbmt.2010.07.027

    View details for Web of Science ID 000286173400003

    View details for PubMedID 20713165

  • Randomized, double-blind trial of fluconazole versus voriconazole for prevention of invasive fungal infection after allogeneic hematopoietic cell transplantation BLOOD Wingard, J. R., Carter, S. L., Walsh, T. J., Kurtzberg, J., Small, T. N., Baden, L. R., Gersten, I. D., Mendizabal, A. M., Leather, H. L., Confer, D. L., Maziarz, R. T., Stadtmauer, E. A., Bolanos-Meade, J., Brown, J., DiPersio, J. F., Boeckh, M., Marr, K. A., Blood & Marrow Transplant Clinical 2010; 116 (24): 5111?18

    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.

    View details for DOI 10.1182/blood-2010-02-268151

    View details for Web of Science ID 000285141200008

    View details for PubMedID 20826719

    View details for PubMedCentralID PMC3012532

  • A 39-Year-Old Woman With Lupus, Myositis, and a Recalcitrant Vasculopathy ARTHRITIS CARE & RESEARCH Sokolove, J., Copland, A., Shirvani, S., Brown, J., Posley, K., Chung, L. 2010; 62 (9): 1351-1356

    View details for DOI 10.1002/acr.20236

    View details for Web of Science ID 000281913400022

    View details for PubMedID 20506174

  • Utility of Influenza Vaccination for Oncology Patients JOURNAL OF CLINICAL ONCOLOGY Pollyea, D. A., Brown, J. M., Horning, S. J. 2010; 28 (14): 2481-2490

    Abstract

    Every fall and winter, patients with cancer and their families ask oncologists whether they should be vaccinated for influenza. This season, with escalating concerns regarding the novel H1N1 influenza virus and its recently approved vaccine, this question has become more frequent and increasingly urgent. The purpose of this article is to review evidence related to the ability of patients with cancer to mount protective immunological responses to influenza vaccination. The literature on immunogenicity in pediatric and adult patients, those with solid tumors and hematologic malignancies, untreated and actively treated patients, and patients receiving biologic agents is summarized and reviewed. In addition, we report on potential strategies to improve the efficacy of influenza vaccination in patients with cancer, such as the timing of vaccination, use of more than a one-shot series, increasing the antigen dose, and the use of adjuvant therapies. We conclude that there is evidence that patients with cancer receiving chemotherapy are able to respond to influenza vaccination, and because this intervention is safe, inexpensive, and widely available, vaccination for seasonal influenza and the novel H1N1 strain is indicated.

    View details for DOI 10.1200/JCO.2009.26.6908

    View details for Web of Science ID 000277389600024

    View details for PubMedID 20385981

  • Prospective Surveillance for Invasive Fungal Infections in Hematopoietic Stem Cell Transplant Recipients, 2001-2006: Overview of the Transplant-Associated Infection Surveillance Network (TRANSNET) Database CLINICAL INFECTIOUS DISEASES Kontoyiannis, D. P., Marr, K. A., Park, B. J., Alexander, B. D., Anaissie, E. J., Walsh, T. J., Ito, J., Andes, D. R., Baddley, J. W., Brown, J. M., Brumble, L. M., Freifeld, A. G., Hadley, S., Herwaldt, L. A., Kauffman, C. A., Knapp, K., Lyon, G. M., Morrison, V. A., Papanicolaou, G., Patterson, T. F., Perl, T. M., Schuster, M. G., Walker, R., Wannemuehler, K. A., Wingard, J. R., Chiller, T. M., Pappas, P. G. 2010; 50 (8): 1091-1100

    Abstract

    The incidence and epidemiology of invasive fungal infections (IFIs), a leading cause of death among hematopoeitic stem cell transplant (HSCT) recipients, are derived mainly from single-institution retrospective studies.The Transplant Associated Infections Surveillance Network, a network of 23 US transplant centers, prospectively enrolled HSCT recipients with proven and probable IFIs occurring between March 2001 and March 2006. We collected denominator data on all HSCTs preformed at each site and clinical, diagnostic, and outcome information for each IFI case. To estimate trends in IFI, we calculated the 12-month cumulative incidence among 9 sequential subcohorts.We identified 983 IFIs among 875 HSCT recipients. The median age of the patients was 49 years; 60% were male. Invasive aspergillosis (43%), invasive candidiasis (28%), and zygomycosis (8%) were the most common IFIs. Fifty-nine percent and 61% of IFIs were recognized within 60 days of neutropenia and graft-versus-host disease, respectively. Median onset of candidiasis and aspergillosis after HSCT was 61 days and 99 days, respectively. Within a cohort of 16,200 HSCT recipients who received their first transplants between March 2001 and September 2005 and were followed up through March 2006, we identified 718 IFIs in 639 persons. Twelve-month cumulative incidences, based on the first IFI, were 7.7 cases per 100 transplants for matched unrelated allogeneic, 8.1 cases per 100 transplants for mismatched-related allogeneic, 5.8 cases per 100 transplants for matched-related allogeneic, and 1.2 cases per 100 transplants for autologous HSCT.In this national prospective surveillance study of IFIs in HSCT recipients, the cumulative incidence was highest for aspergillosis, followed by candidiasis. Understanding the epidemiologic trends and burden of IFIs may lead to improved management strategies and study design.

    View details for DOI 10.1086/651263

    View details for Web of Science ID 000275645900003

    View details for PubMedID 20218877

  • Comparison of polymerase chain reaction of polymorphonuclear leukocytes and plasma identifies patients who control cytomegalovirus infection after hematopoietic cell transplantation CLINICAL INFECTIOUS DISEASES Vana, M. L., Formankova, D., Cha, S., Sharma, A., Potena, L., Brown, J. M., Mocarski, E. S. 2008; 47 (4): 535-539

    Abstract

    By use of an automated polymerase chain reaction test of plasma and a qualitative polymerase chain reaction assay on polymorphonuclear leukocytes, we identified a subgroup of hematopoietic cell transplant recipients who were able to control cytomegalovirus infection early after hematopoietic cell transplantation without antiviral therapy. Thirty-one percent of patients had cytomegalovirus DNA detected by qualitative polymerase chain reaction assay but had no cytomegalovirus DNA detected by the automated test; this group maintained a lower peak cytomegalovirus load, compared with the group of patients who had cytomegalovirus DNA detected by both tests (P = .03), suggesting a greater degree of functional immune reconstitution.

    View details for DOI 10.1086/590151

    View details for Web of Science ID 000257755700020

    View details for PubMedID 18611158

  • The impact of regulatory T cells on T-cell immunity following hematopoietic cell transplantation BLOOD Nguyen, V. H., Shashidhar, S., Chang, D. S., Ho, L., Kambham, N., Bachmann, M., Brown, J. M., Negrin, R. S. 2008; 111 (2): 945-953

    Abstract

    Regulatory T cells (Tregs) prevent graft-versus-host disease (GvHD) by inhibiting the proliferation and function of conventional T cells (Tcons). However, the impact of Tregs on T-cell development and immunity following hematopoietic cell transplantation (HCT) is unknown. Using a murine GvHD model induced by Tcons, we demonstrate that adoptive transfer of Tregs leads to (1) abrogration of GvHD, (2) preservation of thymic and peripheral lymph node architecture, and (3) an accelerated donor lymphoid reconstitution of a diverse TCR-Vbeta repertoire. The resultant enhanced lymphoid reconstitution in Treg recipients protects them from lethal cytomegalovirus (MCMV) infection. By contrast, mice that receive Tcons alone have disrupted lymphoid organs from GvHD and remain lymphopenic with a restricted TCR-Vbeta repertoire and rapid death on MCMV challenge. Lymphocytes from previously infected Treg recipients generate secondary response specific to MCMV, indicating long-term protective immunity with transferred Tregs. Thymectomy significantly reduces survival after MCMV challenge in Treg recipients compared with euthymic controls. Our results indicate that Tregs enhance immune reconstitution by preventing GvHD-induced damage of the thymic and secondary lymphoid microenvironment. These findings provide new insights into the role of Tregs in affording protection to lymphoid stromal elements important for T-cell immunity.

    View details for DOI 10.1182/blood-2007-07-103895

    View details for PubMedID 17916743

  • Cytomegalovirus MCK-2 controls mobilization and recruitment of myeloid progenitor cells to facilitate dissemination BLOOD Noda, S., Aguirre, S. A., Bitmansour, A., Brown, J. M., Sparer, T. E., Huang, J., Mocarski, E. S. 2006; 107 (1): 30-38

    Abstract

    Murine cytomegalovirus encodes a secreted, pro-inflammatory chemokine-like protein, MCK-2, that recruits leukocytes and facilitates viral dissemination. We have shown that MCK-2-enhanced recruitment of myelomonocytic leukocytes with an immature phenotype occurs early during infection and is associated with efficient viral dissemination. Expression of MCK-2 drives the mobilization of a population of leukocytes from bone marrow that express myeloid marker Mac-1 (CD11b), intermediate levels of Gr-1 (Ly6 G/C), platelet-endothelial-cell adhesion molecule-1 (PECAM-1, CD31), together with heterogeneous levels of stem-cell antigen-1 (Sca-1, Ly-6 A /E). Recombinant MCK-2 mediates recruitment of this population even in the absence of viral infection. Recruitment of this cell population and viral dissemination via the bloodstream to salivary glands proceeds normally in mice that lack CCR2 and MCP-1 (CCL2), suggesting that recruitment of macrophages is not a requisite component of pathogenesis. Thus, a systemic impact of MCK-2 enhances the normal host response and causes a marked increase in myelomonocytic recruitment with an immature phenotype to initial sites of infection. Mobilization influences levels of virus dissemination via the bloodstream to salivary glands and is dependent on a myelomonocytic cell type other than mature macrophages.

    View details for Web of Science ID 000234235200012

    View details for PubMedID 16046529

  • Risks and outcomes of invasive fungal infections in pediatric patients undergoing allogeneic hematopoietic cell transplantation BONE MARROW TRANSPLANTATION Dvorak, C. C., Steinbach, W. J., Brown, J. M., Agarwal, R. 2005; 36 (7): 621-629

    Abstract

    Invasive fungal infections (IFI) are the leading cause of infectious mortality in adult patients undergoing hematopoietic cell transplantation (HCT) after myeloablative conditioning, but the extent of this problem in the pediatric population is unclear. We retrospectively examined risk factors for IFI among 120 consecutive pediatric patients undergoing allogeneic HCT at a single center. The incidence of proven or probable IFI in pediatric patients during the first year after allogeneic HCT was 13%, comparable to the rate reported in adult patients; however, unlike IFI in adult patients, the majority of IFI in children occurred within the first month after transplantation. The primary risk factors for IFI were duration of neutropenia, age greater than 10 years, transplant for severe aplastic anemia or Fanconi anemia, and high-dose corticosteroid administration for 10 days or longer. IFI were more likely to be successfully treated (42%, 5/12 patients) in pediatric HCT recipients when compared to previous reports of adult recipients. Nonrelapse mortality was estimated at 17% (20/120 patients) after allogeneic HCT, of which 35% (seven patients) were directly attributed to IFI. Thus, IFI is a significant cause of nonrelapse mortality in children undergoing allogeneic HCT and more effective strategies are needed to prevent and treat IFI.

    View details for DOI 10.1038/sj.bmt.1705113

    View details for Web of Science ID 000231877200009

    View details for PubMedID 16044133

  • Stepwise development of committed progenitors in the bone marrow that generate functional T cells in the absence of the thymus JOURNAL OF IMMUNOLOGY Garcia-Ojeda, M. E., Dejbakhsh-Jones, S., Chatterjea-Matthes, D., Mukhopadhyay, A., Bitmansour, A., Weissman, I. L., Brown, J. M., Strober, S. 2005; 175 (7): 4363-4373

    Abstract

    We identified committed T cell progenitors (CTPs) in the mouse bone marrow that have not rearranged the TCRbeta gene; express a variety of genes associated with commitment to the T cell lineage, including GATA-3, T cell-specific factor-1, Cbeta, and Id2; and show a surface marker pattern (CD44+ CD25- CD24+ CD5-) that is similar to the earliest T cell progenitors in the thymus. More mature committed intermediate progenitors in the marrow have rearranged the TCR gene loci, express Valpha and Vbeta genes as well as CD3epsilon, but do not express surface TCR or CD3 receptors. CTPs, but not progenitors from the thymus, reconstituted the alphabeta T cells in the lymphoid tissues of athymic nu/nu mice. These reconstituted T cells vigorously secreted IFN-gamma after stimulation in vitro, and protected the mice against lethal infection with murine CMV. In conclusion, CTPs in wild-type bone marrow can generate functional T cells via an extrathymic pathway in athymic nu/nu mice.

    View details for Web of Science ID 000232092600027

    View details for PubMedID 16177077

  • Treatment of verruca vulgaris with topical cidofovir in an immunlocompromised patient: a case report and review of the literature TRANSPLANT INFECTIOUS DISEASE Cha, S., Johnston, L., Natkunam, Y., Brown, J. 2005; 7 (3-4): 158-161

    Abstract

    Lesions caused by verrucus vulgaris are commonly refractory to therapy and may become large, painful, or disfiguring in immunocompromised patients. Cidofovir is a potent nucleoside analog antiviral agent shown to have in vitro and in vivo activity against a broad spectrum of DNA viruses. We report a successful use of topical cidofovir to treat verruca vulgaris lesions in a highly immunocompromised patient, who was not considered a candidate for conventional therapy.

    View details for Web of Science ID 000236936200012

    View details for PubMedID 16390407

  • Exogenous administration of immunomodulatory therapies in hematopoietic cell transplantation: an infectious diseases perspective CURRENT OPINION IN INFECTIOUS DISEASES Brown, J. M. 2005; 18 (4): 352-358

    Abstract

    In contrast to the recipient of a solid organ transplantation, the immunological competence of recipients of hematopoietic cell transplantation does not correlate well with the administration of non-corticosteroid immunosuppressive agents. This apparent paradox reflects the unique and dynamic conglomeration of factors that affect immune reconstitution after hematopoietic cell transplantation. The following is the second part of a review of the recent primary literature regarding exogenous immunomodulatory influences as they pertain to infections in the setting of hematopoietic cell transplantation.The main themes of published primary research from 2004 to the present include the influence of exogenously administered immunomodulatory agents on infectious complications after hematopoietic cell transplantation.The use of immunomodulatory agents such as monoclonal antibodies directed against lymphocyte antigens in the treatment of hematopoietic malignancy has greatly expanded during the past decade. Separate trials of the potential utility of these agents, particularly in the reduction of graft-versus-host disease, in the setting of hematopoietic cell transplantation have yielded encouraging results. Given the infancy of these new approaches, it is not possible to make definitive statements regarding the relative risk of serious infection with each therapy. It is clear that a reduction in regimen-related non-infectious complications or mortality does not necessarily ensure a reduction in clinically significant infections. Improvements in early diagnostic and therapeutic options for these infections now bring us to an era of understanding pathogens such as cytomegalovirus as probes of the functional reconstitution of immunity.

    View details for Web of Science ID 000230812700011

    View details for PubMedID 15985834

  • The influence of the conditions of hematopoietic cell transplantation on infectious complications CURRENT OPINION IN INFECTIOUS DISEASES Brown, J. M. 2005; 18 (4): 346-351

    Abstract

    The multitude of factors that influence the risk of infection after hematopoietic cell transplantation has been further complicated by the rapid evolution of this therapy in the past 5 years. The degree to which functional immune reconstitution has been achieved reflects the equilibrium reached by the immune systems of the recipient and donor in the context of host non-hematopoietic tissue. Thus immunomodulatory influences on the recipient and the transplanted graft, both before and after hematopoietic cell transplantation, have a profound influence on the incidence and severity of infection. This review of the recent literature contributes to our understanding of how the conditions of hematopoietic cell transplantation influence the timing and nature of infectious complications.The main themes of published primary research from 2004 to the present focus on non-myeloablative conditioning regimens and their effects on immune reconstitution after hematopoietic cell transplantation.A plethora of clinical trials are ongoing, focused on the outcome after conditioning regimens designed to result in less regimen-related toxicity while preserving or enhancing the graft-versus-tumor effect. Given the infancy of these new approaches, it is not possible to make definitive statements regarding the relative risk of serious infection with each therapy. It is clear that a reduction in regimen-related non-infectious complications or mortality does not necessarily ensure a reduction in clinically significant infections. Improvements in early diagnostic and therapeutic options for these infections now bring us to an era of understanding pathogens as probes of the functional reconstitution of immunity.

    View details for Web of Science ID 000230812700010

    View details for PubMedID 15985833

  • Single infusion of myeloid progenitors reduces death from Aspergillus fumigatus following chemotherapy-induced neutropenia BLOOD Bitmansour, A., Cao, T. M., Chao, S., Shashidhar, S., Brown, J. M. 2005; 105 (9): 3535-3537

    Abstract

    Hematopoietic progenitors committed to the myeloid lineage, the common myeloid and granulocyte-monocyte progenitors (CMP/GMP), have been shown to protect against opportunistic pathogens following myeloablative radiation; however, the efficacy of this approach has not been studied in the setting of chemotherapy-induced neutropenia. In this mouse model, the infusion of CMP/GMP on the day after 5-fluorouracil (5-FU) administration (D+1) resulted in a significant increase in the number of splenic neutrophils by D+8 when compared with 5-FU-only controls (P = .02), the majority of which were CMP/GMP-derived (54%). Moreover, 19% and 28% of neutrophils in the blood and bone marrow, respectively, were CMP/GMP-derived. Survival following intranasal challenge with the fungus Aspergillus fumigatus was significantly higher in CMP/GMP-infused mice than the controls (56% and 33% respectively; P = .019). Thus, a single infusion of CMP/GMP enhances tissue neutrophil content and increases survival against a lethal challenge with A fumigatus in the setting of chemotherapy-induced neutropenia.

    View details for DOI 10.1182/blood-2004-2004-07-2676

    View details for Web of Science ID 000228797400029

    View details for PubMedID 15576478

    View details for PubMedCentralID PMC1895020

  • Rapamycin (sirolimus) for treatment of chronic graft-versus-host disease BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION Johnston, L. J., Brown, J., Shizuru, J. A., Stockerl-Goldstein, K. E., Stuart, M. J., Blume, K. G., Negrin, R. S., Chao, N. J. 2005; 11 (1): 47-55

    Abstract

    We conducted a phase II trial in 19 chronic graft-versus-host disease (cGVHD) patients with rapamycin, calcineurin inhibitors, and prednisone with the goals of controlling cGVHD, reducing prednisone use, and defining the safety of this regimen. Rapamycin was begun as second-line (n = 9) or more than second-line (n = 10) therapy. With a median follow-up of 42 months, 16 patients were evaluable for response. Nine patients discontinued rapamycin because of poor compliance/patient request (n = 2) or an adverse event (n = 7), 3 of whom were not evaluable because of withdrawal at < or =1 month or noncompliance. The adverse events included serum creatinine > or =2.4 mg/dL (n = 4), hemolytic uremic syndrome (n = 2), and relapse of malignancy (n = 1). Fifteen of 16 evaluable patients had a clinical response. Five of the 16 discontinued the drug, and 1 died of relapsed leukemia. Of the 10 patients who continued rapamycin, 2 discontinued and 1 successfully tapered all systemic immunosuppression. Three of the 10 developed progressive cGVHD with tapering immunosuppression; all responded to resumption of prior medications. Four of the 10 patients required alternate therapy for persistent or progressive cGVHD while receiving rapamycin; prednisone was discontinued (n = 2) or tapered at the time of progressive disease (n = 2). Seventeen of 19 original patients were alive. One death was due to relapsed malignancy, and 1 was due to congestive heart failure. In this report of rapamycin as cGVHD therapy, there is evidence of rapamycin's efficacy. Given the significant toxicities described, investigation of altered administration of rapamycin and calcineurin inhibitors should be pursued in future cGVHD trials.

    View details for DOI 10.1016/j.bbmt.2004.10.004

    View details for PubMedID 15625544

  • Fungal infections in bone marrow transplant patients CURRENT OPINION IN INFECTIOUS DISEASES Brown, J. M. 2004; 17 (4): 347-352

    Abstract

    Invasive fungal infections have become the leading infectious cause of death in recipients of hematopoietic cell transplantation. Several factors have led to a renaissance in the study of invasive fungal infections. The growing incidence of both commonly encountered as well as emerging pathogens and the lethality of these infections coupled with the unprecedented number of available broad-spectrum antifungal drugs has lent a renewed vigor and enthusiasm to attempts to understand the pathogenesis of these diseases and, by doing so, improve prevention, diagnosis, and treatment. The following is a review of the primary research published from 2003 to the present that is pertinent to invasive fungal infection in the setting of hematopoietic cell transplantation.The main themes of published primary research during 2003 to the present include the efficacy and tolerability of antifungal prophylaxis, epidemiologic analyses of risk factors following nonmyeloablative preparative regimens, and more-detailed analyses of nonmyeloid immune responses.Although few definitive recommendations emerged from the studies during the review period, these investigations do contribute to a greater understanding of the immunobiology of invasive fungal infection and of the utility and limitations of newer antifungal agents in the prophylaxis or treatment of invasive fungal infection.

    View details for DOI 10.1097/01.qco0000136935.13662.af

    View details for Web of Science ID 000223033000011

    View details for PubMedID 15241080

  • Common lymphoid progenitors rapidly engraft and protect against lethal murine cytomegalovirus infection after hematopoietic stem cell transplantation BLOOD Arber, C., Bitmansour, A., Sparer, T. E., Higgins, J. P., Mocarski, E. S., Weissman, I. L., Shizuru, J. A., Brown, J. M. 2003; 102 (2): 421-428

    Abstract

    Lymphoid deficiency after allogeneic hematopoietic cell transplantation (HCT) results in increased susceptibility to infection; however, transplantation of mature lymphocytes frequently results in a serious complication known as graft-versus-host disease (GVHD). Here we demonstrate in mice that both congenic as well as allogeneic transplantation of low numbers of highly purified common lymphoid progenitors (CLPs)-a rare population of lymphoid-lineage-committed bone marrow cells-accelerates immune reconstitution after lethal irradiation and rescue with hematopoietic stem cells (HSCs). After congenic transplantation, 3 x 10(3) CLPs protected against murine cytomegalovirus (MCMV) infection at a level roughly equivalent to 107 unfractionated lymph node cells. In the allogeneic model of matched unrelated donor HSC transplantation, cotransplantation of 3 x 10(3) CLPs protected thymus-bearing as well as thymectomized hosts from MCMV infection and attenuated disease severity. Immunohistochemistry in combination with antibody depletion of T and natural killer (NK) cells confirmed that CLP-derived as well as residual host lymphocytes contribute to antiviral protection. Importantly, transplantation of allogeneic CLPs provided a durable antiviral immunity without inducing GVHD. These data support the potential for composing grafts with committed progenitors to reduce susceptibility to viral infection following HCT.

    View details for DOI 10.1182/blood-2002-12-3834

    View details for Web of Science ID 000184083500010

    View details for PubMedID 12663447

  • Myeloid progenitors protect against invasive aspergillosis and Pseudomonas aeruginosa infection following hematopoietic stem cell transplantation BLOOD Bitmansour, A., Burns, S. M., Traver, D., Akashi, K., Contag, C. H., Weissman, I. L., Brown, J. M. 2002; 100 (13): 4660-4667

    Abstract

    Myelotoxic treatments for oncologic diseases are often complicated by neutropenia, which renders patients susceptible to potentially lethal infections. In these studies of murine hematopoietic stem cell transplantation (HSCT), cotransplantation of lineage-restricted progenitors known as common myeloid progenitors (CMP) and granulocyte-monocyte progenitors (GMP) protects against death following otherwise lethal challenge with either of 2 pathogens associated with neutropenia: Aspergillus fumigatus and Pseudomonas aeruginosa. Cotransplantation of CMP/GMP resulted in a significant and rapid increase in the absolute number of myeloid cells in the spleen, most of which were derived from the donor CMP/GMP. Despite persistent peripheral neutropenia, improved survival correlated with the measurable appearance of progenitor-derived myeloid cells in the spleen. A marked reduction or elimination of tissue pathogen load was confirmed by culture and correlated with survival. Localization of infection by P aeruginosa and extent of disease was also assessed by in vivo bioluminescent imaging using a strain of P aeruginosa engineered to constitutively express a bacterial luciferase. Imaging confirmed that transplantation with a graft containing hematopoietic stem cells and CMP/GMP reduced the bacterial load as early as 18 hours after infection. These results demonstrate that enhanced reconstitution of a tissue myeloid pool offers protection against lethal challenge with serious fungal and bacterial pathogens.

    View details for DOI 10.1182/blood-2002-05-1552

    View details for Web of Science ID 000179759800058

    View details for PubMedID 12393415

  • Immunity to infections following hematopoietic cell transplantation CURRENT OPINION IN IMMUNOLOGY Brown, J. M., Weissman, I. L., Shizuru, J. A. 2001; 13 (4): 451-457

    Abstract

    Hematopoietic cell transplantation has progressed from the use of unpurified bone marrow cells or mobilized peripheral blood cells to the use of purified stem cells and progenitor cells. These kinds of transplants can be designed to provide not only hematopoietic rescue but also augmented innate and acquired immunity.

    View details for Web of Science ID 000169648600010

    View details for PubMedID 11498301

  • Reassessing the organization of the UL42-UL43 region of the human cytomegalovirus strain AD169 genome VIROLOGY Mocarski, E. S., Prichard, M. N., TAN, C. S., Brown, J. M. 1997; 239 (1): 169-175

    Abstract

    A polymorphism in the UL42-UL43 region of the human cytomegalovirus genome has been characterized by nucleotide sequence analysis, revealing a 929-bp insertion following nt 54,612 relative to the published strain AD169-UK genome sequence (M.S. Chee et al., 1990, Curr. Top. Microbiol Immunol. 154, 125-170). Although AD169-UK exhibited polymorphism in this genomic region, other CMV strains (Towne, Toledo, and AD169-ATCC) carried only the newly characterized longer form. The additional sequence altered the assignment of UL42 and UL43 open reading frames. UL42 decreased in size from 157 to 125 codons, retaining 76 of the previously reported carboxyl terminal codons, and UL43 increased in size from 187 to 423 codons, retaining 185 of the previously reported amino terminal codons. This additional sequence makes UL43 a more conserved betaherpesvirus US22 family member. Only AD169-UK exhibited restriction fragment length polymorphism in this region, suggesting that a deletion occurred during the propagation of this strain in cell culture. The additional sequence should be considered a bona fide part of the cytomegalovirus genome and the AD169 genome size should be corrected to 230,283 bp.

    View details for Web of Science ID 000071139000016

    View details for PubMedID 9426456

  • SELECTABLE INSERTION AND DELETION MUTAGENESIS OF THE HUMAN CYTOMEGALOVIRUS GENOME USING THE ESCHERICHIA-COLI GUANOSINE PHOSPHORIBOSYL TRANSFERASE (GPT) GENE JOURNAL OF GENERAL VIROLOGY Greaves, R. F., Brown, J. M., VIEIRA, J., Mocarski, E. S. 1995; 76: 2151-2160

    Abstract

    We describe the mutagenesis of the IRSI-US5 region of the human cytomegalovirus genome, demonstrating the potential of the E. coli guanosine phosphoribosyl transferase (gpt) gene as a selectable marker for insertion and deletion mutagenesis of high passage (AD169, Towne) as well as low passage (Toledo) strains of virus. Despite evidence suggesting that the US3 gene product may play a regulatory role, disruption of this gene with a gpt insert had no effect on growth of any of these strains of virus in resting or dividing human fibroblasts, or in human thymus plus liver implants in SCID-hu mice. Transcripts of the gpt gene, under control of the herpes simplex virus thymidine kinase promoter adjacent to the US3 enhancer in the viral genome, accumulated with delayed early (beta) kinetics. Mutants with deletions in the IRS1 and US3-US5 regions were isolated by back-selection against gpt with the drug 6-thioguanine by growing virus in human Lesch-Nyhan (hypoxanthine-guanine phosphoribosyl transferase deficient) skin fibroblasts immortalized with human papillomavirus oncogenes. Thus, we demonstrate a dependable method for insertion and deletion mutagenesis that can be applied to any region of the viral genome.

    View details for Web of Science ID A1995RT16600005

    View details for PubMedID 7561752

  • DRAMATIC INTERSTRAIN DIFFERENCES IN THE REPLICATION OF HUMAN CYTOMEGALOVIRUS IN SCID-HU MICE JOURNAL OF INFECTIOUS DISEASES Brown, J. M., Kaneshima, H., Mocarski, E. S. 1995; 171 (6): 1599-1603

    Abstract

    The ability of a low-passage strain (Toledo) and laboratory strains (AD169 and Towne) of human cytomegalovirus to replicate in SCID-hu (thymus plus liver) mice were compared. At a time of peak replication, 14 days after inoculation, the Toledo strain grew 2-3 orders of magnitude better than any laboratory strain, a difference reflecting the number of infected thymic stromal cells in the implants. The growth property of the Toledo strain was stable through serial passage and plaque purification. The AD169-ATCC strain failed to grow at all, while an independently maintained stock of this strain obtained from the United Kingdom replicated to low levels, suggesting that divergence had occurred during propagation in different locations. This work predicts the existence of viral genetic determinant(s) for growth in tissues that are lost during propagation in culture.

    View details for Web of Science ID A1995RB29800030

    View details for PubMedID 7769298

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