Publications by authors named "Michael J Boeckh"

34 Publications

A human coronavirus evolves antigenically to escape antibody immunity.

PLoS Pathog 2021 04 8;17(4):e1009453. Epub 2021 Apr 8.

Basic Sciences and Computational Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.

There is intense interest in antibody immunity to coronaviruses. However, it is unknown if coronaviruses evolve to escape such immunity, and if so, how rapidly. Here we address this question by characterizing the historical evolution of human coronavirus 229E. We identify human sera from the 1980s and 1990s that have neutralizing titers against contemporaneous 229E that are comparable to the anti-SARS-CoV-2 titers induced by SARS-CoV-2 infection or vaccination. We test these sera against 229E strains isolated after sera collection, and find that neutralizing titers are lower against these "future" viruses. In some cases, sera that neutralize contemporaneous 229E viral strains with titers >1:100 do not detectably neutralize strains isolated 8-17 years later. The decreased neutralization of "future" viruses is due to antigenic evolution of the viral spike, especially in the receptor-binding domain. If these results extrapolate to other coronaviruses, then it may be advisable to periodically update SARS-CoV-2 vaccines.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.ppat.1009453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8031418PMC
April 2021

Cytomegalovirus-specific T-cell Reconstitution following Letermovir Prophylaxis after Hematopoietic Cell Transplantation.

Blood 2021 Mar 3. Epub 2021 Mar 3.

University of Washington, United States.

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. We compared polyfunctional CMV-specific T-cell responses in a prospective cohort of allogeneic HCT recipients who received letermovir to controls who received PCR-guided preemptive therapy prior to the introduction of letermovir. Thirteen-color flow cytometry was used to assess T-cell responses at three months post-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 (COMPASS). Letermovir use and reduction in 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 adjusting 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 CMV shedding rate was associated with greater CD4+ responses to IE-1. In conclusion, our study provides initial evidence that letermovir may delay CMV-specific cellular reconstitution, possibly due to decreased CMV antigen exposure. Evaluating T-cell polyfunctionality may identify patients at risk for late CMV infection after HCT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2020009396DOI Listing
March 2021

Immunogenicity of Inactivated Varicella Zoster Vaccine in Autologous Hematopoietic Stem Cell Transplant Recipients and Patients With Solid or Hematologic Cancer.

Open Forum Infect Dis 2020 Jul 2;7(7):ofaa172. Epub 2020 Jun 2.

Merck & Co., Inc., Kenilworth, New Jersey, USA.

Background: In phase 3 trials, inactivated varicella zoster virus (VZV) vaccine (ZV) was well tolerated and efficacious against herpes zoster (HZ) in autologous hematopoietic stem cell transplant (auto-HSCT) recipients and patients with solid tumor malignancies receiving chemotherapy (STMc) but did not reduce HZ incidence in patients with hematologic malignancies (HMs). Here, we describe ZV immunogenicity from these studies.

Methods: Patients were randomized to ZV or placebo (4 doses). Immunogenicity was assessed by glycoprotein enzyme-linked immunosorbent assay (gpELISA) and VZV interferon (IFN)-γ enzyme-linked immunospot (ELISPOT) assay in patients receiving all 4 doses without developing HZ at the time of blood sampling.

Results: Estimated geometric mean fold rise ratios (ZV/placebo) by gpELISA and IFN-y ELISPOT ~28 days post-dose 4 were 2.02 (95% confidence interval [CI], 1.53-2.67) and 5.41 (95% CI, 3.60-8.12) in auto-HSCT recipients; 1.88 (95% CI, 1.79-1.98) and 2.10 (95% CI, 1.69-2.62) in patients with STMc; and not assessed and 2.35 (95% CI, 1.81-3.05) in patients with HM.

Conclusions: ZV immunogenicity was directionally consistent with clinical efficacy in auto-HSCT recipients and patients with STMc even though HZ protection and VZV immunity were not statistically correlated. Despite a lack of clinical efficacy in patients with HM, ZV immunogenicity was observed in this population. Immunological results did not predict vaccine efficacy in these 3 populations.

Clinical Trial Registration: NCT01229267, NCT01254630.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ofid/ofaa172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7336559PMC
July 2020

Late infectious complications in hematopoietic cell transplantation survivors: a population-based study.

Blood Adv 2020 04;4(7):1232-1241

Department of Pediatrics, University of Washington, Seattle Children's Hospital, Seattle, WA.

Few studies have compared the incidence of infections occurring ≥2 years after hematopoietic cell transplant (HCT) with other cancer patients and the general population. In this study, ≥2-year HCT survivors who were Washington residents treated from 1992 through 2009 (n = 1792; median age, 46 years; 52% allogeneic; 90% hematologic malignancies) were matched to individuals from the state cancer registry (n = 5455, non-HCT) and driver's license files (n = 16 340; Department of Licensing [DOL]). Based on hospital and death registry codes, incidence rate ratios (IRRs; 95% confidence interval [CI]) of infections by organism type and organ system were estimated using Poisson regression. With 7-year median follow-up, the incidence rate (per 1000 person-years) of all infections was 65.4 for HCT survivors vs 39.6 for the non-HCT group (IRR, 1.6; 95% CI, 1.3-1.9) and 7.2 for DOL (IRR, 10.0; 95% CI, 8.3-12.1). Bacterial and fungal infections were each 70% more common in HCT vs non-HCT cancer survivors (IRR, 1.7; P < .01), whereas the risk for viral infection was lower (IRR, 1.4; P = .07). Among potentially vaccine-preventable organisms, the IRR was 3.0 (95% CI, 2.1-4.3) vs the non-HCT group. Although the incidences of all infections decreased with time, the relative risk in almost all categories remained significantly increased in ≥5-year HCT survivors vs other groups. Risk factors for late infection included history of relapse and for some infections, history of chronic graft-versus-host disease. Providers caring for HCT survivors should maintain vigilance for infections and ensure adherence to antimicrobial prophylaxis and vaccination guidelines.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2020001470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160274PMC
April 2020

Oral brincidofovir decreases the incidence of HHV-6B viremia after allogeneic HCT.

Blood 2020 04;135(17):1447-1451

Fred Hutchinson Cancer Research Center, Seattle, WA.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2019004315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7180083PMC
April 2020

Durable preservation of antiviral antibodies after CD19-directed chimeric antigen receptor T-cell immunotherapy.

Blood Adv 2019 11;3(22):3590-3601

Department of Medicine, University of Washington, Seattle, WA.

The long-term effects of CD19-targeted chimeric antigen receptor-modified T-cell immunotherapy (CD19-CARTx) for B-cell malignancies on humoral immunity are unclear. We examined antiviral humoral immunity in 39 adults with B-cell malignancies who achieved durable complete remission without additional therapy for >6 months after CD19-CARTx. Despite CD19+ B-cell aplasia in all patients, the incidence of viral infections occurring >90 days post-CD19-CARTx was low (0.91 infections per person-year). Because long-lived plasma cells are CD19- and should not be direct targets of CD19-targeted chimeric antigen receptor T cells, we tested the hypothesis that humoral immunity was preserved after CD19-CARTx based on linear mixed-effects models of changes in serum total immunoglobulin G (IgG) concentration, measles IgG concentration, and the number of viruses or viral epitopes to which serum IgG was directed (the "antivirome") using the novel VirScan assay. Samples were tested pre-CD19-CARTx and ∼1, 6, and 12 months post-CD19-CARTx. Although total IgG concentration was lower post-CD19-CARTx (mean change, -17.5%), measles IgG concentration was similar (mean change, 1.2%). Only 1 participant lost measles seroprotection post-CD19-CARTx but had undergone allogeneic hematopoietic cell transplantation before CD19-CARTx. The antivirome was also preserved, with mean absolute losses of 0.3 viruses and 6 viral epitopes detected between pre- and post-CD19-CARTx samples. Most participants gained IgG to ≥2 epitopes for ≥2 viruses, suggesting that humoral immunity to some viruses may be maintained or recover after successful CD19-CARTx. These findings may differ in children. Studies of immunoglobulin replacement and vaccination after CARTx are warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2019000717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6880890PMC
November 2019

Predictive Value of Respiratory Viral Detection in the Upper Respiratory Tract for Infection of the Lower Respiratory Tract With Hematopoietic Stem Cell Transplantation.

J Infect Dis 2020 01;221(3):379-388

Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

Background: Hematopoietic cell transplant (HCT) recipients are frequently infected with respiratory viruses (RVs) in the upper respiratory tract (URT), but the concordance between URT and lower respiratory tract (LRT) RV detection is not well characterized.

Methods: Hematopoietic cell transplant candidates and recipients with respiratory symptoms and LRT and URT RV testing via multiplex PCR from 2009 to 2016 were included. Logistic regression models were used to analyze risk factors for LRT RV detection.

Results: Two-hundred thirty-five HCT candidates or recipients had URT and LRT RV testing within 3 days. Among 115 subjects (49%) positive for a RV, 37% (42 of 115) had discordant sample pairs. Forty percent (17 of 42) of discordant pairs were positive in the LRT but negative in the URT. Discordance was common for adenovirus (100%), metapneumovirus (44%), rhinovirus (34%), and parainfluenza virus type 3 (28%); respiratory syncytial virus was highly concordant (92%). Likelihood of LRT detection was increased with URT detection (oods ratio [OR] = 73.7; 95% confidence interval [CI], 26.7-204) and in cytomegalovirus-positive recipients (OR = 3.70; 95% CI, 1.30-10.0).

Conclusions: High rates of discordance were observed for certain RVs. Bronchoalveolar lavage sampling may provide useful diagnostic information to guide management in symptomatic HCT candidates and recipients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/infdis/jiz470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7107470PMC
January 2020

Effect of Recombinant Zoster Vaccine on Incidence of Herpes Zoster After Autologous Stem Cell Transplantation: A Randomized Clinical Trial.

JAMA 2019 07;322(2):123-133

Duke University Medical Center, Durham, North Carolina.

Importance: Herpes zoster, a frequent complication following autologous hematopoietic stem cell transplantation (HSCT), is associated with significant morbidity. A nonlive adjuvanted recombinant zoster vaccine has been developed to prevent posttransplantation zoster.

Objective: To assess the efficacy and adverse event profile of the recombinant zoster vaccine in immunocompromised autologous HSCT recipients.

Design, Setting, And Participants: Phase 3, randomized, observer-blinded study conducted in 167 centers in 28 countries between July 13, 2012, and February 1, 2017, among 1846 patients aged 18 years or older who had undergone recent autologous HSCT.

Interventions: Participants were randomized to receive 2 doses of either recombinant zoster vaccine (n = 922) or placebo (n = 924) administered into the deltoid muscle; the first dose was given 50 to 70 days after transplantation and the second dose 1 to 2 months thereafter.

Main Outcomes And Measures: The primary end point was occurrence of confirmed herpes zoster cases.

Results: Among 1846 autologous HSCT recipients (mean age, 55 years; 688 [37%] women) who received 1 vaccine or placebo dose, 1735 (94%) received a second dose and 1366 (74%) completed the study. During the 21-month median follow-up, at least 1 herpes zoster episode was confirmed in 49 vaccine and 135 placebo recipients (incidence, 30 and 94 per 1000 person-years, respectively), an incidence rate ratio (IRR) of 0.32 (95% CI, 0.22-0.44; P < .001), equivalent to 68.2% vaccine efficacy. Of 8 secondary end points, 3 showed significant reductions in incidence of postherpetic neuralgia (vaccine, n=1; placebo, n=9; IRR, 0.1; 95% CI, 0.00-0.78; P = .02) and of other prespecified herpes zoster-related complications (vaccine, n=3; placebo, n=13; IRR, 0.22; 95% CI, 0.04-0.81; P = .02) and in duration of severe worst herpes zoster-associated pain (vaccine, 892.0 days; placebo, 6275.0 days; hazard ratio, 0.62; 95% CI, 0.42-0.89; P = .01). Five secondary objectives were descriptive. Injection site reactions were recorded in 86% of vaccine and 10% of placebo recipients, of which pain was the most common, occurring in 84% of vaccine recipients (grade 3: 11%). Unsolicited and serious adverse events, potentially immune-mediated diseases, and underlying disease relapses were similar between groups at all time points.

Conclusions And Relevance: Among adults who had undergone autologous HSCT, a 2-dose course of recombinant zoster vaccine compared with placebo significantly reduced the incidence of herpes zoster over a median follow-up of 21 months.

Trial Registration: ClinicalTrials.gov Identifier: NCT01610414.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jama.2019.9053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6618796PMC
July 2019

A Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial of Oral Brincidofovir for Cytomegalovirus Prophylaxis in Allogeneic Hematopoietic Cell Transplantation.

Biol Blood Marrow Transplant 2019 02 4;25(2):369-381. Epub 2018 Oct 4.

Department of Medicine, University of Washington, Seattle, Washington; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.

Cytomegalovirus (CMV) infection is a common complication of allogeneic hematopoietic cell transplantation (HCT). In this trial, we randomized adult CMV-seropositive HCT recipients without CMV viremia at screening 2:1 to receive brincidofovir or placebo until week 14 post-HCT. Randomization was stratified by center and risk of CMV infection. Patients were assessed weekly through week 15 and every third week thereafter through week 24 post-HCT. Patients who developed clinically significant CMV infection (CS-CMVi; CMV viremia requiring preemptive therapy or CMV disease) discontinued the study drug and began anti-CMV treatment. The primary endpoint was the proportion of patients with CS-CMVi through week 24 post-HCT; patients who discontinued the trial or with missing data were imputed as primary endpoint events. Between August 2013 and June 2015, 452 patients were randomized at a median of 15 days after HCT and received study drug. The proportion of patients who developed CS-CMVi or were imputed as having a primary endpoint event through week 24 was similar between brincidofovir-treated patients and placebo recipients (155 of 303 [51.2%] versus 78 of 149 [52.3%]; odds ratio, .95 [95% confidence interval, .64 to 1.41]; P = .805); fewer brincidofovir recipients developed CMV viremia through week 14 compared with placebo recipients (41.6%; P < .001). Serious adverse events were more frequent among brincidofovir recipients (57.1% versus 37.6%), driven by acute graft-versus-host disease (32.3% versus 6.0%) and diarrhea (6.9% versus 2.7%). Week 24 all-cause mortality was 15.5% among brincidofovir recipients and 10.1% among placebo recipients. Brincidofovir did not reduce CS-CMVi by week 24 post-HCT and was associated with gastrointestinal toxicity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbmt.2018.09.038DOI Listing
February 2019

Inactivated varicella zoster vaccine in autologous haemopoietic stem-cell transplant recipients: an international, multicentre, randomised, double-blind, placebo-controlled trial.

Lancet 2018 05 24;391(10135):2116-2127. Epub 2018 May 24.

Stanford University School of Medicine, Stanford, CA, USA.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S0140-6736(18)30631-7DOI Listing
May 2018

Graft-Derived Reconstitution of Mucosal-Associated Invariant T Cells after Allogeneic Hematopoietic Cell Transplantation.

Biol Blood Marrow Transplant 2018 02 9;24(2):242-251. Epub 2017 Oct 9.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Medicine, University of Washington, Seattle, Washington.

Mucosal-associated invariant T (MAIT) cells express a semi-invariant Vα7.2 T cell receptor (TCR) that recognizes ligands from distinct bacterial and fungal species. In neonates, MAIT cells proliferate coincident with gastrointestinal (GI) bacterial colonization. In contrast, under noninflammatory conditions adult MAIT cells remain quiescent because of acquired regulation of TCR signaling. Effects of inflammation and the altered GI microbiota after allogeneic hematopoietic cell transplantation (HCT) on MAIT cell reconstitution have not been described. We conducted an observational study of MAIT cell reconstitution in myeloablative (n = 41) and nonmyeloablative (n = 66) allogeneic HCT recipients and found that despite a rapid and early increase to a plateau at day 30 after HCT, MAIT cell numbers failed to normalize for at least 1 year. Cord blood transplant recipients and those who received post-HCT cyclophosphamide for graft versus host disease (GVHD) prophylaxis had profoundly impaired MAIT cell reconstitution. Sharing of TCRβ gene sequences between MAIT cells isolated from HCT grafts and blood of recipients after HCT showed early MAIT cell reconstitution was due at least in part to proliferation of MAIT cells transferred in the HCT graft. Inflammatory cytokines were required for TCR-dependent MAIT cell proliferation, suggesting that bacterial Vα7.2 TCR ligands might promote MAIT cell reconstitution after HCT. Robust MAIT cell reconstitution was associated with an increased GI abundance of Blautia spp. MAIT cells suppressed proliferation of conventional T cells consistent with a possible regulatory role. Our data identify modifiable factors impacting MAIT cell reconstitution that could influence the risk of GVHD after HCT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbmt.2017.10.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5806215PMC
February 2018

Infusion-Compatible Antibiotic Formulations for Rapid Administration to Improve Outcomes in Cancer Outpatients With Severe Sepsis and Septic Shock: The Sepsis STAT Pack.

J Natl Compr Canc Netw 2017 04;15(4):457-464

Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center

Patients with cancer are at high risk for severe sepsis and septic shock (SS/SSh), and a delay in receiving effective antibiotics is strongly associated with mortality. Delays are due to logistics of clinic flow and drug delivery. In an era of increasing antimicrobial resistance, combination therapy may be superior to monotherapy for patients with SS/SSh. At the Seattle Cancer Care Alliance, we implemented the Sepsis STAT Pack (SSP) program to simplify timely and effective provision of empiric antibiotics and other resuscitative care to outpatients with cancer with suspected SS/SSh before hospitalization. Over a 49-month period from January 1, 2008, through January 31, 2012, a total of 162 outpatients with cancer received the intervention. A retrospective cohort study was conducted to determine outcomes, including mortality and adverse events associated with the use of a novel care bundle designed for compatibility of broad-spectrum antibiotics and other supportive care administered concurrently via rapid infusion at fixed doses. Of 162 sequential patients with cancer and suspected SS/SSh who received the SSP, 71 (44%) were diagnosed with SS/SSh. Median age was 53 years and 65% were men; 141 (87%) had hematologic malignancies, 77 (48%) were transplant recipients, and 80 (49%) were neutropenic. Median time to completion of antibiotics was 111 minutes (interquartile range, 60-178 minutes). A total of 71 patients (44%) had bacteremia and 17% of 93 isolates were multidrug-resistant. Possibly related nephrotoxicity occurred in 7 patients, and 30-day mortality occured in 6 of 160 patients (4%), including 3 of 71 (4%) with SS/SSh. Risk of developing SSh or death within 30 days increased 18% (95% CI, 4%-34%) for each hour delay to completion of antibiotics (=.01). Rapidly administered combination antibiotics and supportive care delivered emergently to ambulatory patients with cancer with suspected SS/SSh was well-tolerated and associated with excellent short-term survival.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6379908PMC
http://dx.doi.org/10.6004/jnccn.2017.0045DOI Listing
April 2017

Genetic risk factors for sclerotic graft-versus-host disease.

Blood 2016 09 16;128(11):1516-24. Epub 2016 Jun 16.

Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA; Department of Medicine, and.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5025901PMC
http://dx.doi.org/10.1182/blood-2016-05-715342DOI Listing
September 2016

Reevaluation of the pretransplant assessment of mortality score after allogeneic hematopoietic transplantation.

Biol Blood Marrow Transplant 2015 May 31;21(5):848-54. Epub 2015 Jan 31.

Division of Clinical Research, Fred Hutchinson Cancer Research Center; Department of Medicine, University of Washington, Seattle, Washington. Electronic address:

The Pretransplant Assessment of Mortality (PAM) score was developed in 2006 to predict risk of mortality after allogeneic hematopoietic cell transplantation (HCT). Transplant practices have evolved during the past decade, suggesting the need to reevaluate the performance of the PAM score. We used statistical modeling to analyze and recalibrate mortality based on overall PAM scores, its components, and conditioning regimen in a retrospective cohort of 1549 patients who had HCT from 2003 through 2009. PAM scores correlated with mortality, but the effect size was smaller in the current study than in previous studies. PAM scores also demonstrated a stronger association with mortality in patients who received myeloablative conditioning than in those who received reduced-intensity conditioning. In contrast to the original study, carbon monoxide diffusing capacity, serum alanine aminotransferase, and serum creatinine concentrations were no longer significantly associated with 2-year mortality, whereas patient and donor cytomegalovirus serology was associated with mortality in the current cohort. Based on our findings, we developed and tested a revised PAM score for clinicians to estimate survival after allogeneic HCT with myeloablative conditioning regimens for patients with hematologic malignancy. Prognostic models such as the PAM score should be updated and recalibrated periodically to accommodate changes in clinical practice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbmt.2015.01.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4408250PMC
May 2015

Management of respiratory viral infections in hematopoietic cell transplant recipients and patients with hematologic malignancies.

Clin Infect Dis 2014 Nov;59 Suppl 5:S344-51

Fred Hutchinson Cancer Research Center University of Washington, Seattle.

Despite preventive strategies and increased awareness, a high incidence of respiratory viral infections still occur in patients with hematologic malignancies (HMs) and in recipients of hematopoietic cell transplant (HCT). Progression of these viral infections to lower respiratory tract may prove fatal, especially in HCT recipients. Increasing evidence on the successful use of ribavirin (alone or in combination with immunomodulators) for the treatment of respiratory syncytial virus infections in HM patients and HCT recipients is available from retrospective studies; however, prospective clinical trials are necessary to establish its efficacy with confidence. The impact on progression to pneumonitis and/or mortality of treating parainfluenza virus infections with available (ribavirin) or investigational (DAS181) antiviral agents still needs to be determined. Influenza infections have been successfully treated with neuraminidase inhibitors (oseltamivir or zanamivir); however, the efficacy of these agents for influenza pneumonia has not been established, and immunocompromised patients are highly susceptible to emergence of antiviral drug resistance, most probably due to prolonged viral shedding. Infection control measures and an appreciation of the complications following respiratory viral infections in immunocompromised patients remain crucial for reducing transmission. Future studies should focus on strategies to identify patients at high risk for increased morbidity and mortality from these infections and to determine the efficacy of novel or available antiviral drugs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cid/ciu623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4303052PMC
November 2014

Prevalence of chromosomally integrated human herpesvirus 6 in patients with human herpesvirus 6-central nervous system dysfunction.

Biol Blood Marrow Transplant 2015 Feb 22;21(2):371-3. Epub 2014 Sep 22.

Division of Allergy and Infectious Diseases, University of Washington, Seattle, Washington; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.

We identified 37 hematopoietic cell transplantation recipients with human herpesvirus 6 (HHV-6) central nervous system dysfunction and tested donor-recipient pairs for chromosomally integrated HHV-6 (ciHHV-6). One patient had ciHHV-6A with possible HHV-6A reactivation and encephalitis. There was no ciHHV-6 enrichment in this group, but larger studies are needed to determine if patients with ciHHV-6 are at increased risk for HHV-6-associated diseases or other complications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbmt.2014.09.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4438705PMC
February 2015

Human herpesvirus 6 can be detected in cerebrospinal fluid without associated symptoms after allogeneic hematopoietic cell transplantation.

J Clin Virol 2014 Oct 12;61(2):289-92. Epub 2014 Jul 12.

Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States; Seattle Children's Research Institute, Seattle, WA, United States.

Background: Human herpesvirus 6 (HHV-6) is an opportunistic pathogen after hematopoietic cell transplantation (HCT) that is associated with central nervous system (CNS) dysfunction.

Objectives: The aim of this study was to determine the frequency and significance of HHV-6 DNA detection in cerebrospinal fluid (CSF) after HCT.

Study Design: We identified patients with HHV-6 DNA in CSF using quantitative PCR. Patients with neurologic symptoms and HHV-6 DNA in CSF without identification of an alternative etiology were categorized as having HHV-6 CNS dysfunction.

Results: Among 3902 allogeneic HCT recipients from 1998 to 2012, 51 of 124 tested patients had HHV-6 DNA in CSF; 37 met criteria for HHV-6 CNS dysfunction and 14 (27%) did not. Patients with an alternative diagnosis had longer time to HHV-6 detection and lower viral load in CSF. Six patients without HHV-6 CNS dysfunction were not treated and had no morbidity attributable to HHV-6. Kaplan-Meier analysis demonstrated poor overall survival among all patients. Variables associated with higher all-cause mortality in a multivariable Cox model included alternative diagnosis (adjusted hazard ratio [aHR], 8.4; 95% CI, 1.7-40.9; P = 0.009) and higher peak plasma viral load (log(10) scale) (aHR, 1.4; 95% CI, 1.1-1.9; P = 0.01).

Conclusion: We identified a number of allogeneic HCT recipients with HHV-6 DNA in CSF who did not meet criteria for HHV-6 CNS dysfunction. All patients had poor survival. Whether CSF HHV-6 DNA detection in patients without associated CNS dysfunction independently contributes to mortality and warrants treatment is unclear; management of these patients warrants further investigation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jcv.2014.07.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4165730PMC
October 2014

Recipient pretransplant inosine monophosphate dehydrogenase activity in nonmyeloablative hematopoietic cell transplantation.

Biol Blood Marrow Transplant 2014 Oct 9;20(10):1544-52. Epub 2014 Jun 9.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; School of Pharmacy, University of Washington, Seattle, Washington. Electronic address:

Mycophenolic acid, the active metabolite of mycophenolate mofetil (MMF), inhibits inosine monophosphate dehydrogenase (IMPDH) activity. IMPDH is the rate-limiting enzyme involved in de novo synthesis of guanosine nucleotides and catalyzes the oxidation of inosine 5'-monophosphate to xanthosine 5'-monophosphate (XMP). We developed a highly sensitive liquid chromatography-mass spectrometry method to quantitate XMP concentrations in peripheral blood mononuclear cells (PMNCs) isolated from the recipient pretransplant and used this method to determine IMPDH activity in 86 nonmyeloablative allogeneic hematopoietic cell transplantation (HCT) patients. The incubation procedure and analytical method yielded acceptable within-sample and within-individual variability. Considerable between-individual variability was observed (12.2-fold). Low recipient pretransplant IMPDH activity was associated with increased day +28 donor T cell chimerism, more acute graft-versus-host disease (GVHD), lower neutrophil nadirs, and more cytomegalovirus reactivation but not with chronic GVHD, relapse, nonrelapse mortality, or overall mortality. We conclude that quantitation of the recipient's pretransplant IMPDH activity in PMNC lysate could provide a useful biomarker to evaluate a recipient's sensitivity to MMF. Further trials should be conducted to confirm our findings and to optimize postgrafting immunosuppression in nonmyeloablative HCT recipients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbmt.2014.05.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4163086PMC
October 2014

Pharmacokinetic and pharmacodynamic analysis of inosine monophosphate dehydrogenase activity in hematopoietic cell transplantation recipients treated with mycophenolate mofetil.

Biol Blood Marrow Transplant 2014 Aug 13;20(8):1121-9. Epub 2014 Apr 13.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; School of Pharmacy, University of Washington, Seattle, Washington. Electronic address:

A novel approach to personalizing postgrafting immunosuppression in hematopoietic cell transplantation (HCT) recipients is evaluating inosine monophosphate dehydrogenase (IMPDH) activity as a drug-specific biomarker of mycophenolic acid (MPA)-induced immunosuppression. This prospective study evaluated total MPA, unbound MPA, and total MPA glucuronide plasma concentrations and IMPDH activity in peripheral blood mononuclear cells (PMNCs) at 5 time points after the morning dose of oral mycophenolate mofetil (MMF) on day +21 in 56 nonmyeloablative HCT recipients. Substantial interpatient variability in pharmacokinetics and pharmacodynamics was observed and accurately characterized by the population pharmacokinetic-dynamic model. IMPDH activity decreased with increasing MPA plasma concentration, with maximum inhibition coinciding with maximum MPA concentration in most patients. The overall relationship between MPA concentration and IMPDH activity was described by a direct inhibitory maximum effect model with an IC50 of 3.23 mg/L total MPA and 57.3 ng/mL unbound MPA. The day +21 IMPDH area under the effect curve (AUEC) was associated with cytomegalovirus reactivation, nonrelapse mortality, and overall mortality. In conclusion, a pharmacokinetic-dynamic model was developed that relates plasma MPA concentrations with PMNC IMPDH activity after an MMF dose in HCT recipients. Future studies should validate this model and confirm that day +21 IMPDH AUEC is a predictive biomarker.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbmt.2014.03.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4099316PMC
August 2014

Nonrelapse mortality and mycophenolic acid exposure in nonmyeloablative hematopoietic cell transplantation.

Biol Blood Marrow Transplant 2013 Aug 6;19(8):1159-66. Epub 2013 May 6.

Department of Pharmacy, School of Pharmacy, University of Washington, Seattle, WA 98195, USA.

We evaluated the pharmacodynamic relationships between mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF), and outcomes in 308 patients after nonmyeloablative hematopoietic cell transplantation. Patients were conditioned with total body irradiation ± fludarabine, received grafts from HLA-matched related (n = 132) or unrelated (n = 176) donors, and received postgrafting immunosuppression with MMF and a calcineurin inhibitor. Total and unbound MPA pharmacokinetics were determined to day 25; maximum a posteriori Bayesian estimators were used to estimate total MPA concentration at steady state (Css). Rejection occurred in 9 patients, 8 of whom had a total MPA Css less than 3 μg/mL. In patients receiving a related donor graft, MPA Css was not associated with clinical outcomes. In patients receiving an unrelated donor graft, low total MPA Css was associated with increased grades III to IV acute graft-versus-host disease and increased nonrelapse mortality but not with day 28 T cell chimerism, disease relapse, cytomegalovirus reactivation, or overall survival. We conclude that higher initial oral MMF doses and subsequent targeting of total MPA Css to greater than 2.96 μg/mL could lower grades III to IV acute graft-versus-host disease and nonrelapse mortality in patients receiving an unrelated donor graft.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbmt.2013.04.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3720781PMC
August 2013

Combination therapy with amantadine, oseltamivir and ribavirin for influenza A infection: safety and pharmacokinetics.

Antivir Ther 2013 21;18(3):377-86. Epub 2012 Dec 21.

Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

Background: Antiviral resistance among influenza A viruses is associated with high morbidity and mortality in immunocompromised hosts. However, treatment strategies for drug-resistant influenza A are not established. A triple-combination antiviral drug (TCAD) regimen consisting of amantadine (AMT), oseltamivir (OSL) and ribavirin (RBV) demonstrated good efficacy in an animal model.

Methods: We first analysed the pharmacokinetics (PKs) of TCAD therapy in healthy volunteers. We then performed a pilot study of TCAD therapy in patients undergoing chemotherapy or haematopoietic cell transplantation. AMT (75 mg), OSL (50 mg) and RBV (200 mg) were administered three times a day for 10 days. The safety and PKs of TCAD therapy were monitored.

Results: The PKs of TCAD therapy in healthy volunteers was shown to be similar to the PKs of each drug individually from a single dose. In the pilot study, six immunocompromised patients received TCAD therapy and one patient received OSL monotherapy. All but one patient completed 10 days of TCAD therapy without side effects; one patient receiving TCAD was withdrawn from the study because of respiratory failure and ultimately recovered. Viral load was decreased after TCAD therapy, despite the presence of either AMT- or OSL-resistant virus in two cases. One patient with 2009 influenza A/H1N1 receiving OSL monotherapy developed confirmed OSL resistance during treatment.

Conclusions: TCAD therapy had similar PKs to each individual antiviral during monotherapy following a single dose and can be administered safely in immunocompromised patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3851/IMP2475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3912210PMC
September 2013

Effect of MHC and non-MHC donor/recipient genetic disparity on the outcome of allogeneic HCT.

Blood 2012 Oct 2;120(14):2796-806. Epub 2012 Aug 2.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2012-04-347286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3466963PMC
October 2012

Efficiency and risk factors for CMV transmission in seronegative hematopoietic stem cell recipients.

Biol Blood Marrow Transplant 2012 Sep 3;18(9):1391-1400. Epub 2012 Mar 3.

Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.

Cytomegalovirus (CMV) transmission via stem cells or marrow in CMV donor seropositive/recipient seronegative (D+/R-) hematopoietic cell transplantation (HCT) is surprisingly inefficient, and factors associated with transmission in these high-risk HCT recipients are unknown. In a retrospective cohort of D+/R- HCT recipients, cumulative incidence curve estimates were used to determine posttransplantation rates of CMV and multivariable Cox proportional models to assess risk factors associated with transmission. A total of 447 patients from 1995 to 2007 were eligible for enrollment. Overall, 85 of 447 (19.0%) acquired CMV at a median of 49 days (IQR 41-60) posttransplantation. CMV disease before day 100 occurred in 6 of 447 (1.3%) patients and in 7 of 447 (1.6%) after day 100. The donor graft, specifically the total nucleated cell count (adjusted hazard ratio [HR] 2.7; 95% confidence interval [CI], 1.4-4.7, P = .0002), was the only factor associated with CMV transmission in multivariable analyses. Notably, the source stem cells (marrow versus peripheral blood stem cell [PBSC]), screening method, and graft-versus-host disease (GVHD) were not associated with transmission. Thus, a highly cellular graft was the only identifiable risk factor associated with CMV transmission, suggesting that viral genomic content of the donor graft determines transmission efficiency in D+/R- HCT recipients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbmt.2012.02.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3572857PMC
September 2012

Intensive strategy to prevent CMV disease in seropositive umbilical cord blood transplant recipients.

Blood 2011 Nov 21;118(20):5689-96. Epub 2011 Sep 21.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2011-06-361618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3217367PMC
November 2011

H275Y mutant pandemic (H1N1) 2009 virus in immunocompromised patients.

Emerg Infect Dis 2011 Apr;17(4):653-60; quiz 765

Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

Most oseltamivir-resistant pandemic (H1N1) 2009 viruses have been isolated from immunocompromised patients. To describe the clinical features, treatment, outcomes, and virologic data associated with infection from pandemic (H1N1) 2009 virus with H275Y mutation in immunocompromised patients, we retrospectively identified 49 hematology-oncology patients infected with pandemic (H1N1) 2009 virus. Samples from 33 of those patients were tested for H275Y genotype by allele-specific real-time PCR. Of the 8 patients in whom H275Y mutations was identified, 1 had severe pneumonia; 3 had mild pneumonia with prolonged virus shedding; and 4 had upper respiratory tract infection, of whom 3 had prolonged virus shedding. All patients had received oseltamivir before the H275Y mutation was detected; 1 had received antiviral prophylaxis. Three patients excreted resistant virus for >60 days. Emergence of oseltamivir resistance is frequent in immunocompromised patients infected with pandemic (H1N1) 2009 virus and can be associated with a wide range of clinical disease and viral kinetics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3201/eid1704.101429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3290123PMC
April 2011

Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of america.

Clin Infect Dis 2011 Feb;52(4):e56-93

Department of Medicine, University of Nebraska Medical Center, Omaha, Nebraska.

This document updates and expands the initial Infectious Diseases Society of America (IDSA) Fever and Neutropenia Guideline that was published in 1997 and first updated in 2002. It is intended as a guide for the use of antimicrobial agents in managing patients with cancer who experience chemotherapy-induced fever and neutropenia. Recent advances in antimicrobial drug development and technology, clinical trial results, and extensive clinical experience have informed the approaches and recommendations herein. Because the previous iteration of this guideline in 2002, we have a developed a clearer definition of which populations of patients with cancer may benefit most from antibiotic, antifungal, and antiviral prophylaxis. Furthermore, categorizing neutropenic patients as being at high risk or low risk for infection according to presenting signs and symptoms, underlying cancer, type of therapy, and medical comorbidities has become essential to the treatment algorithm. Risk stratification is a recommended starting point for managing patients with fever and neutropenia. In addition, earlier detection of invasive fungal infections has led to debate regarding optimal use of empirical or preemptive antifungal therapy, although algorithms are still evolving. What has not changed is the indication for immediate empirical antibiotic therapy. It remains true that all patients who present with fever and neutropenia should be treated swiftly and broadly with antibiotics to treat both gram-positive and gram-negative pathogens. Finally, we note that all Panel members are from institutions in the United States or Canada; thus, these guidelines were developed in the context of North American practices. Some recommendations may not be as applicable outside of North America, in areas where differences in available antibiotics, in the predominant pathogens, and/or in health care-associated economic conditions exist. Regardless of venue, clinical vigilance and immediate treatment are the universal keys to managing neutropenic patients with fever and/or infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cid/cir073DOI Listing
February 2011

Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 Update by the Infectious Diseases Society of America.

Clin Infect Dis 2011 Feb 4;52(4):427-31. Epub 2011 Jan 4.

Department of Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA.

This document updates and expands the initial Infectious Diseases Society of America (IDSA) Fever and Neutropenia Guideline that was published in 1997 and first updated in 2002. It is intended as a guide for the use of antimicrobial agents in managing patients with cancer who experience chemotherapy-induced fever and neutropenia. Recent advances in antimicrobial drug development and technology, clinical trial results, and extensive clinical experience have informed the approaches and recommendations herein. Because the previous iteration of this guideline in 2002, we have a developed a clearer definition of which populations of patients with cancer may benefit most from antibiotic, antifungal, and antiviral prophylaxis. Furthermore, categorizing neutropenic patients as being at high risk or low risk for infection according to presenting signs and symptoms, underlying cancer, type of therapy, and medical comorbidities has become essential to the treatment algorithm. Risk stratification is a recommended starting point for managing patients with fever and neutropenia. In addition, earlier detection of invasive fungal infections has led to debate regarding optimal use of empirical or preemptive antifungal therapy, although algorithms are still evolving. What has not changed is the indication for immediate empirical antibiotic therapy. It remains true that all patients who present with fever and neutropenia should be treated swiftly and broadly with antibiotics to treat both gram-positive and gram-negative pathogens. Finally, we note that all Panel members are from institutions in the United States or Canada; thus, these guidelines were developed in the context of North American practices. Some recommendations may not be as applicable outside of North America, in areas where differences in available antibiotics, in the predominant pathogens, and/or in health care-associated economic conditions exist. Regardless of venue, clinical vigilance and immediate treatment are the universal keys to managing neutropenic patients with fever and/or infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cid/ciq147DOI Listing
February 2011

Evaluating the impact of antithymocyte globulin on lung function at 1 year after allogeneic stem cell transplantation.

Biol Blood Marrow Transplant 2011 May 22;17(5):703-9. Epub 2010 Aug 22.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

The use of antithymocyte globulin (ATG) in hematopoietic stem cell transplantation (HSCT) conditioning regimens has reduced the incidence of graft-versus-host disease, particularly in its chronic form. The impact of this approach on the prevention of lung dysfunction has not been well characterized, however. We performed a retrospective analysis of pulmonary function in patients who underwent HSCT after conditioning with oral busulfan followed by either cyclophosphamide or fludarabine with or without the addition of ATG. A total of 393 patients were included; 75 patients received ATG, and 318 did not. No differences between the 2 groups were seen in the mean percentage of the predicted values for forced expiratory volume in 1 second (FEV(1)), forced vital capacity (FVC), total lung capacity, and lung CO diffusing capacity at 80 days or 1 year after transplantation. However, the mean value of FEV(1)/FVC ratio at 1 year was higher in the patients who received ATG. The difference in mean change in pulmonary function parameters from baseline to 1 year post-HSCT was statistically nonsignificant for all parameters except FEV(1)/FVC ratio, which demonstrated less decline in the ATG group. The risk of developing severe airflow obstruction or a restrictive pattern was similar in the 2 treatment groups at 1 year post-HSCT. Incorporation of ATG into the HSCT conditioning regimen provided protection against a decline in FEV(1)/FVC ratio but did not decrease the risk of other pulmonary events that we evaluated within the first year after HSCT. Further evaluations in larger numbers of patients are needed to better clarify the role of ATG in the development of delayed pulmonary complications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbmt.2010.08.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3224742PMC
May 2011

The effect of imatinib on cytomegalovirus reactivation in hematopoietic cell transplantation.

Clin Infect Dis 2009 Dec;49(11):e120-3

Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.

In vitro studies have shown possible antiviral effects of tyrosine kinase inhibitors. In a retrospective study, we show that use of the tyrosine kinase inhibitor imatinib does not appear to reduce cytomegalovirus reactivation during the first 100 days after transplantation in a cohort of hematopoietic cell transplant recipients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1086/648120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2779734PMC
December 2009