Publications by authors named "Nicolas C Issa"

29 Publications

  • Page 1 of 1

Safety and reactogenicity of the recombinant zoster vaccine after allogeneic hematopoietic cell transplantation.

Blood Adv 2021 Mar;5(6):1585-1593

Department of Infectious Disease and.

Allogeneic hematopoietic cell transplantation (HCT) recipients are at increased risk for varicella zoster virus (VZV) reactivation and associated complications. A nonlive adjuvanted recombinant zoster vaccine (RZV) has been developed to prevent herpes zoster (HZ), but there are no recommendations for use in this population. In this single-center prospective observational cohort study, we assessed the safety and reactogenicity of RZV, as well as incidence of graft-versus-host disease (GVHD) and confirmed cases of HZ after vaccination. Between December of 2018 and June of 2020, patients aged ≥18 years received 2 doses of RZV between 9 and 24 months after HCT, with the doses separated by ≥8 weeks. One hundred and fifty-eight patients (mean age, 55 years; 42% women) received ≥1 dose (total vaccinated cohort), and 150 patients (95%) received 2 doses (modified total vaccinated cohort). Solicited reactions occurred in 92.1% of patients (grade 3, 32.5%), owing mostly to injection site pain, which occurred in 86% (grade 3, 16%). The cumulative incidence of GVHD in the peri-vaccination period was no different than in historical controls (adjusted incidence rate ratio, 1.05; 95% confidence interval, 0.8-1.38). There were 4 cases of HZ in the total vaccinated cohort (2.5%) and 3 cases in the modified total vaccinated cohort (28.3/1000 person-years). Among recipients of allogeneic HCT, RZV was safe, tolerable, and did not increase rates of GVHD. Future clinical trials are needed to determine the immunogenicity and efficacy of RZV in this population.
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http://dx.doi.org/10.1182/bloodadvances.2020003749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993108PMC
March 2021

Pneumocystis jirovecii pneumonia and institutional prophylaxis practices in CLL patients treated with BTK inhibitors.

Blood Adv 2020 04;4(7):1458-1463

Department of Medicine, Brigham and Women's Hospital, Boston, MA.

Opportunistic infections (OIs), such as Pneumocystis jirovecii pneumonia (PJP), have been reported in chronic lymphocytic leukemia (CLL) patients treated with ibrutinib, and are an important cause of morbidity and mortality. Currently, there are no international consensus guidelines regarding the use of antimicrobial prophylaxis for OIs, and in particular PJP, in CLL patients treated with Bruton tyrosine kinase inhibitors (BTKi's). We evaluated the frequency of PJP in CLL patients at our institution who were treated with BTKi's, and assessed the impact of prophylaxis on reducing the risk of PJP. We identified 217 patients treated with BTKi's, consisting of 3 cohorts: 143 patients on either BTKi monotherapy with ibrutinib or acalabrutinib, 17 patients receiving ibrutinib combination therapy with umbralisib as part of a clinical trial, and 57 patients receiving ibrutinib in combination with standard chemotherapy, also as part of a clinical trial. Forty-one percent of patients on BTKi monotherapy received prophylaxis, which was given at the discretion of the treating physician. The prevalence of PJP in all patients not on prophylaxis was 3.4% (3 of 87), and, specifically in BTKi-monotherapy patients not on prophylaxis, the PJP prevalence was 2.4% (2 of 85). PJP prophylaxis was effective, as there were no cases of PJP in patients on prophylaxis (0 of 130). The relatively low prevalence of PJP in our study population suggests that routine prophylaxis may not be indicated in CLL patients on BTKi therapy.
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http://dx.doi.org/10.1182/bloodadvances.2020001678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160295PMC
April 2020

Poxvirus Vectored Cytomegalovirus Vaccine to Prevent Cytomegalovirus Viremia in Transplant Recipients: A Phase 2, Randomized Clinical Trial.

Ann Intern Med 2020 03 11;172(5):306-316. Epub 2020 Feb 11.

City of Hope Comprehensive Cancer Center and the Beckman Research Institute of City of Hope, Duarte, California (C.L., J.L., C.R.L., Q.Z., J.M., T.K., A.D., N.H., S.F., D.J.D.).

Background: Triplex vaccine was developed to enhance cytomegalovirus (CMV)-specific T cells and prevent CMV reactivation early after hematopoietic stem cell transplant (HCT).

Objective: To determine the safety and efficacy of Triplex.

Design: First-in-patient, phase 2 trial. (ClinicalTrials.gov: NCT02506933).

Setting: 3 U.S. HCT centers.

Participants: 102 CMV-seropositive HCT recipients at high risk for CMV reactivation.

Intervention: Intramuscular injections of Triplex or placebo were given on days 28 and 56 after HCT. Triplex is a recombinant attenuated poxvirus (modified vaccinia Ankara) expressing immunodominant CMV antigens.

Measurements: The primary outcomes were CMV events (CMV DNA level ≥1250 IU/mL, CMV viremia requiring antiviral treatment, or end-organ disease), nonrelapse mortality, and severe (grade 3 or 4) graft-versus-host disease (GVHD), all evaluated through 100 days after HCT, and grade 3 or 4 adverse events (AEs) within 2 weeks after vaccination that were probably or definitely attributable to injection.

Results: A total of 102 patients (51 per group) received the first vaccination, and 91 (89.2%) received both vaccinations (46 Triplex and 45 placebo). Reactivation of CMV occurred in 5 Triplex (9.8%) and 10 placebo (19.6%) recipients (hazard ratio, 0.46 [95% CI, 0.16 to 1.4]; P = 0.075). No Triplex recipient died of nonrelapse causes during the first 100 days or had serious AEs, and no grade 3 or 4 AEs related to vaccination were observed within 2 weeks after vaccination. Incidence of severe acute GVHD after injection was similar between groups (hazard ratio, 1.1 [CI, 0.53 to 2.4]; P = 0.23). Levels of long-lasting, pp65-specific T cells with effector memory phenotype were significantly higher in Triplex than placebo recipients.

Limitation: The lower-than-expected incidence of CMV events in the placebo group reduced the power of the trial.

Conclusion: No vaccine-associated safety concerns were identified. Triplex elicited and amplified CMV-specific immune responses, and fewer Triplex-vaccinated patients had CMV viremia.

Primary Funding Source: National Cancer Institute and Helocyte.
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http://dx.doi.org/10.7326/M19-2511DOI Listing
March 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.
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http://dx.doi.org/10.1001/jama.2019.9053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6618796PMC
July 2019

Severe Herpes Zoster Requiring Intravenous Antiviral Treatment in Allogeneic Hematopoietic Cell Transplantation Recipients on Standard Acyclovir Prophylaxis.

Biol Blood Marrow Transplant 2019 08 17;25(8):1642-1647. Epub 2019 Apr 17.

Department of Infectious Diseases, Brigham and Women's Hospital, Boston, Massachusetts; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Allogeneic hematopoietic cell transplantation (HCT) recipients are at increased risk for varicella zoster virus (VZV) reactivation and associated complications. The incidence, timing, and risk factors for severe herpes zoster (HZ) are not well described in the era of acyclovir (ACV) prophylaxis. We performed a retrospective cohort study of all patients who underwent first allogeneic HCT between October 2006 and December 2015 at our institution. Patients were followed until December 2017 for the development of severe HZ, defined as necessitating administration of i.v. antiviral medication. Out of 2163 patients who underwent allogeneic HCT, 22 (1.0%) developed severe HZ at a rate of 1 per 228 person-years, including dermatomal/multidermatomal disease (n = 5), disseminated skin disease (n = 5), HZ ophthalmicus (n = 4), meningitis/encephalitis (n = 4), pneumonia (n = 2), viremia (n = 1), and erythema multiforme (n = 1). Severe HZ infection occurred in a bimodal distribution during the early peri-HCT period and at 12 to 24 months post-HCT (median, 12.7 months). Twelve patients (54.5%) were compliant with ACV prophylaxis at the time of HZ diagnosis. Eleven patients (50%) died during the study period, only 2 of whom (9.1%) with active VZV infection. Mortality was higher in patients on immunosuppressive therapy (62.5% versus 16.7%; P = .045) and with concurrent graft-versus-host disease (75.0% versus 35.7%; P= .044). These data suggest that severe HZ remains an important consideration despite ACV prophylaxis.
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http://dx.doi.org/10.1016/j.bbmt.2019.04.015DOI Listing
August 2019

Plateletpheresis-associated lymphopenia in frequent platelet donors.

Blood 2019 02 14;133(6):605-614. Epub 2018 Nov 14.

Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.

More than 1 million apheresis platelet collections are performed annually in the United States. After 2 healthy plateletpheresis donors were incidentally found to have low CD4 T-lymphocyte counts, we investigated whether plateletpheresis causes lymphopenia. We conducted a cross-sectional single-center study of platelet donors undergoing plateletpheresis with the Trima Accel, which removes leukocytes continuously with its leukoreduction system chamber. We recruited 3 groups of platelet donors based on the total number of plateletpheresis sessions in the prior 365 days: 1 or 2, 3 to 19, or 20 to 24. CD4 T-lymphocyte counts were <200 cells per microliter in 0/20, 2/20, and 6/20 donors, respectively ( = .019), and CD8 T-lymphocyte counts were low in 0/20, 4/20, and 11/20 donors, respectively ( < .001). The leukoreduction system chamber's lymphocyte-extraction efficiency was ∼15% to 20% for all groups. Immunophenotyping showed decreases in naive CD4 T-lymphocyte and T helper 17 (Th17) cell percentages, increases in CD4 and CD8 effector memory, Th1, and regulatory T cell percentages, and stable naive CD8 and Th2 percentages across groups. T-cell receptor repertoire analyses showed similar clonal diversity in all groups. Donor screening questionnaires supported the good health of the donors, who tested negative at each donation for multiple pathogens, including HIV. Frequent plateletpheresis utilizing a leukoreduction system chamber is associated with CD4 and CD8 T-cell lymphopenia in healthy platelet donors. The mechanism may be repeated extraction of these cells during plateletpheresis. The cytopenias do not appear to be harmful.
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http://dx.doi.org/10.1182/blood-2018-09-873125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6367645PMC
February 2019

Isavuconazole for the treatment of invasive fungal disease in patients receiving ibrutinib.

Leuk Lymphoma 2019 02 24;60(2):527-530. Epub 2018 Jul 24.

a Division of Infectious Diseases, Department of Medicine , Brigham and Women's Hospital , Boston , MA , USA.

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http://dx.doi.org/10.1080/10428194.2018.1485913DOI Listing
February 2019

Safety and immunogenicity of conjugate quadrivalent meningococcal vaccination after hematopoietic cell transplantation.

Blood Adv 2018 06;2(11):1272-1276

Division of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital, and.

Immunization with the conjugated quadrivalent (serogroups A, C, Y, and W-135) meningococcal vaccine (MCV4) after hematopoietic cell transplantation (HCT) is recommended. However, immune responses to MCV4 have not been prospectively studied after HCT. We conducted a vaccine response study among 67 adults who received 1 MCV4 dose a year after autologous or allogeneic HCT from January to September 2014. Pre- and postvaccination serogroup serum bactericidal antibody (SBA) titers were measured a median of 57 days after vaccination. Serogroup-specific responses were defined as a fourfold increase in SBA titer with postvaccination titers ≥1:8. Prior to vaccination, 44 (65.7%) patients had no protective titers (<1:8) to any meningococcal serogroup, and 3 (4.5%) patients had protective titers to all 4 serogroups. The median serogroup-specific postvaccination SBA titers were 1:2048 for A, 1:64 for C, 1:128 for W-135, and 1:128 for Y ( < .001 for all pre- and postvaccination pairwise comparisons; similar among serogroups, Spearman ρ 0.5-0.6, < .0001). Among serogroup-specific nonimmune patients prior to vaccination, serogroup-specific response rates were 76.9%, 65.5%, 51.7%, and 65% to serogroups A, C, W-135, and Y, respectively. One dose of MCV4 elicited protective titers in the majority of patients. These data suggest that a second vaccine dose may be beneficial.
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http://dx.doi.org/10.1182/bloodadvances.2018018911DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5998919PMC
June 2018

Risk of hepatitis B virus reactivation in patients treated with ibrutinib.

Blood 2018 04 28;131(17):1987-1989. Epub 2018 Feb 28.

Division of Infectious Diseases, Brigham and Women's Hospital, Boston, MA; and.

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http://dx.doi.org/10.1182/blood-2018-01-826495DOI Listing
April 2018

Safety of live-attenuated measles-mumps-rubella and herpes zoster vaccination in multiple myeloma patients on maintenance lenalidomide or bortezomib after autologous hematopoietic cell transplantation.

Bone Marrow Transplant 2018 07 9;53(7):942-945. Epub 2018 Feb 9.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Attenuated live virus vaccinations are generally recommended 24 months following hematopoietic cell transplantation (HCT) in patients not receiving immunosuppressive therapy. To date, there are no data regarding the safety of live-attenuated herpes zoster or measles-mumps-rubella (MMR) vaccinations in multiple myeloma patients on maintenance lenalidomide or bortezomib following autologous HCT. One hundred thirty-seven multiple myeloma patients on maintenance lenalidomide or bortezomib post-auto-HCT who received either MMR or herpes zoster vaccine were analyzed and any adverse events documented in the medical record in the 42 days following vaccination were recorded. Patients were vaccinated a median of 25 months (range, 18-62) post transplant. The most common post-vaccination adverse event was upper respiratory tract infection (18/137 patients); no rash attributed to vaccine strains or other adverse outcomes potentially related to the vaccines were identified. MMR and herpes zoster vaccination were safe and well-tolerated in this cohort.
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http://dx.doi.org/10.1038/s41409-018-0112-xDOI Listing
July 2018

Dasatinib Use and Risk of Cytomegalovirus Reactivation After Allogeneic Hematopoietic-Cell Transplantation.

Clin Infect Dis 2017 Aug;65(3):510-513

Division of Infectious Diseases, Brigham and Women's Hospital.

Viral infections have been reported with dasatinib use, but its cytomegalovirus risk after hematopoietic-cell transplantation (HCT) is not known. We found that post-HCT dasatinib use increased the risk of cytomegalovirus reactivation (adjusted hazard ratio, 7.65; 95% confidence interval, 1.84-31.7), controlling for acute graft-versus-host disease, in 109 patients with Philadelphia-chromosome-positive malignancies.
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http://dx.doi.org/10.1093/cid/cix325DOI Listing
August 2017

Green herring syndrome: bacterial infection in patients with mucormycosis cavitary lung disease.

Open Forum Infect Dis 2014 Mar 12;1(1):ofu014. Epub 2014 May 12.

Divisions of Infectious Diseases, Department of Medicine ; Department of Medical Oncology , Dana-Farber Cancer Institute , Boston, Massachusetts ; Harvard Medical School , Boston, Massachusetts.

Mucormycosis is a life-threatening fungal disease in patients with hematological malignancies. The diagnosis of pulmonary mucormycosis is particularly challenging. We describe 3 mucormycosis cases with an uncommon presentation in patients whose cavitary lung disease was attributed to well documented bacterial infection, although evolution and reassessment established mucormycosis as the underlying disease.
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http://dx.doi.org/10.1093/ofid/ofu014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4324200PMC
March 2014

Serologic response to hepatitis B vaccination among lung transplantation candidates.

Transplantation 2014 Sep;98(6):676-9

1 Division of Infectious Diseases, 2 Department of Pharmacy, 3 Division of Pulmonary Medicine and Critical Care, Brigham & Women's Hospital, 4 Harvard Medical School, Boston, MA. 5 Address correspondence to: Alicia Galar Pharm.D., Ph.D., Division of Infectious Diseases, Brigham and Women's Hospital, 75 Francis St., PBB-A4, Boston, MA 02115.

Background: Optimal hepatitis B (HBV) vaccination strategies for lung transplantation (LT) candidates are not well established.

Methods: LT candidates with negative anti-HBs and anti-HBc antibody titers at baseline who received standard-dose HBV vaccination (Recombivax-HB 10 mcg/mL or Engerix-B 20 mcg/mL) administered at months 0, 1, and 6 or an accelerated vaccination schedule on days 0, 7 to 14, and 21 to 28 between June 1988 and October 2012 were studied. Patients who were more likely to undergo LT within 6 months of evaluation received the accelerated vaccination schedule starting in August 2009.

Results: Ninety-six HBV-seronegative patients who completed the vaccination series and had postvaccination anti-HBs titers available were identified. Median age was 60 years; 55.2% were female, and 92.7% were white. Underlying lung diseases included COPD (44.8%), idiopathic pulmonary fibrosis (22.9%), interstitial lung disease (15.6%), and cystic fibrosis (8.3%). The overall anti-HBs response rate was 54.2%. There was no significant difference in vaccine responses between accelerated and standard vaccination schedules (54.2% vs. 54.1%; P=1.0). Patients who received steroids or other immunosuppressants before transplantation had lower response rates compared with those who did not (38.9% vs. 63.3%; P=0.03).

Conclusions: Better vaccination strategies to improve response rate are needed in this population. The accelerated HBV vaccination schedule elicited similar anti-HBs responses as the standard schedule and could be advantageous in this population, given current organ allocation practices, and it could allow repeat vaccination series for initial nonresponders before transplantation.
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http://dx.doi.org/10.1097/TP.0000000000000128DOI Listing
September 2014

Pneumonia in the immunocompromised host.

Curr Opin Pulm Med 2014 May;20(3):272-9

aDivision of Infectious Diseases, Brigham and Women's Hospital bDepartment of Medical Oncology, Dana-Farber Cancer Institute cHarvard Medical School, Boston, Massachusetts, USA.

Purpose Of Review: Novel treatment modalities for previously fatal diseases, including newer chemotherapeutic and biologic agents and the expansion of the indications for solid organ and stem cell transplantation, have resulted in prolonged patient survival and a significant increase in the population of immunocompromised hosts (ICHs).

Recent Findings: This review discusses the increasing spectrum of opportunistic infections in the ICH, the general approach for early diagnosis and treatment of pulmonary infections in this population, and the current and novel diagnostic modalities available to establish a rapid and specific microbiologic diagnosis, focusing on recent controversies and advances.

Summary: Early diagnosis and prompt initiation of effective therapy for infection help reduce morbidity in ICHs. Advances in diagnostic assays using nonculture-based methods, such as nucleic acid amplification, may allow for earlier targeted therapy. Invasive procedures including bronchoscopy and biopsy remain essential and should be vigorously pursued in ICHs given the broad differential diagnosis of possible pulmonary pathogens in this population, and the need to establish a specific diagnosis to allow accurate targeted therapy.
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http://dx.doi.org/10.1097/MCP.0000000000000051DOI Listing
May 2014

Live attenuated varicella-zoster vaccine in hematopoietic stem cell transplantation recipients.

Biol Blood Marrow Transplant 2014 Feb 22;20(2):285-7. Epub 2013 Nov 22.

Division of Infectious Diseases, Brigham and Women's Hospital, Boston, Massachusetts; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts.

Hematopoietic stem cell transplantation (HSCT) recipients are at risk for varicella-zoster virus (VZV) reactivation. Vaccination may help restore VZV immunity; however, the available live attenuated VZV vaccine (Zostavax) is contraindicated in immunocompromised hosts. We report our experience with using a single dose of VZV vaccine in 110 adult autologous and allogeneic HSCT recipients who were about 2 years after transplantation, free of graft-versus-host disease, and not receiving immunosuppression. One hundred eight vaccine recipients (98.2%) had no clinically apparent adverse events with a median follow-up period of 9.5 months (interquartile range, 6 to 16; range, 2 to 28). Two vaccine recipients (1.8%) developed a skin rash (one zoster-like rash with associated pain, one varicella-like) within 42 days post-vaccination that resolved with antiviral therapy. We could not confirm if these rashes were due to vaccine (Oka) or wild-type VZV. No other possible cases of VZV reactivation have occurred with about 1178 months of follow-up. Live attenuated zoster vaccine appears generally safe in this population when vaccinated as noted; the overall vaccination risk needs to be weighed against the risk of wild-type VZV disease in this high-risk population.
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http://dx.doi.org/10.1016/j.bbmt.2013.11.013DOI Listing
February 2014

Postoperative antibacterial prophylaxis for the prevention of infectious complications associated with tube thoracostomy in patients undergoing elective general thoracic surgery: a double-blind, placebo-controlled, randomized trial.

JAMA Surg 2013 May;148(5):440-6

Divisions of Infectious Diseases, Brigham and Women’s Hospital, Boston, Massachusetts, USA.

Objective: To determine whether extended postoperative antibacterial prophylaxis for patients undergoing elective thoracic surgery with tube thoracostomy reduces the risk of infectious complications compared with preoperative prophylaxis only.

Design: Prospective, randomized, double-blind, placebo-controlled trial.

Setting: Brigham and Women's Hospital, an 800-bed tertiary care teaching hospital in Boston, Massachusetts.

Participants: A total of 251 adult patients undergoing elective thoracic surgery requiring tube thoracostomy between April 2008 and April 2011.

Interventions: Patients received preoperative antibacterial prophylaxis with cefazolin sodium (or other drug if the patient was allergic to cefazolin). Postoperatively, patients were randomly assigned (at a 1:1 ratio) using a computer-generated randomization sequence to receive extended antibacterial prophylaxis (n = 125) or placebo (n = 126) for 48 hours or until all thoracostomy tubes were removed, whichever came first.

Main Outcome Measures: The combined occurrence of surgical site infection, empyema, pneumonia, and Clostridium difficile colitis by postoperative day 28.

Results: A total of 245 patients were included in the modified intention-to-treat analysis (121 in the intervention group and 124 in the placebo group). Thirteen patients (10.7%) in the intervention group and 8 patients (6.5%) in the placebo group had a primary end point (risk difference, -4.3% [95% CI, -11.3% to 2.7%]; P = .26). Six patients (5.0%) in the intervention group and 5 patients (4.0%) in the placebo group developed surgical site infections (risk difference, -0.93% [95% CI, -6.1% to 4.3%]; P = .77). Seven patients (5.8%) in the intervention group and 3 patients (2.4%) in the placebo group developed pneumonia (risk difference, -3.4% [95% CI, -8.3% to 1.6%]; P = .21). One patient in the intervention group developed empyema. No patients experienced C difficile colitis.

Conclusions: Extended postoperative antibacterial prophylaxis for patients undergoing elective thoracic surgery requiring tube thoracostomy did not reduce the number of infectious complications compared with preoperative prophylaxis only.

Trial Registration: clinicaltrials.gov Identifier: NCT00818766.
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http://dx.doi.org/10.1001/jamasurg.2013.1372DOI Listing
May 2013

Current issues in vaccines for adult patients with hematologic malignancies.

J Natl Compr Canc Netw 2012 Nov;10(11):1447-54; quiz 1454

Division of Infectious Diseases, Brigham & Women's Hospital; Dana-Farber Cancer Institute, 75 Francis St., Boston, MA 02115, USA.

Vaccination is an important strategy for preventing infections in patients with hematologic malignancies. Hematopoietic cell transplant (HCT) recipients have diminished immunity against vaccine-preventable diseases after transplantation. Optimal timing for initiating immunization in the context of hematologic malignancies and after HCT, however, is not well defined, and data on the magnitude and duration of immune response to vaccines in this population are lacking. Factors such as degree of immunosuppression, administration of monoclonal antibodies, time after HCT, and presence or absence of chronic graft-versus-host disease may influence the immune response to vaccines and may pose safety concerns for certain vaccines, such as live-attenuated immunogens. Patients who received certain monoclonal antibodies (eg, rituximab, alemtuzumab) less than 6 months before vaccination have poorer immune responses to vaccines. New advancements in vaccine development are warranted to improve safety and immunogenicity of vaccination in immunocompromised patients.
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http://dx.doi.org/10.6004/jnccn.2012.0147DOI Listing
November 2012

A targeted peritransplant antifungal strategy for the prevention of invasive fungal disease after lung transplantation: a sequential cohort analysis.

Transplantation 2012 Aug;94(3):281-6

Division of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.

Background: Lung transplant recipients are at high risk of invasive fungal disease (IFD), particularly invasive aspergillosis and candidiasis. The antifungal strategy that optimally balances effective reduction of IFD with a minimum of toxicity remains undefined; universal triazole prophylaxis is common at lung transplantation (LT) centers, despite the well-known toxicities and costs of this approach.

Methods: We implemented an antifungal strategy in March 2007 targeted at LT recipients at highest risk for IFD based on our institutional epidemiology. All patients received inhaled amphotericin B during their initial LT hospitalization, bilateral lung transplant recipients received 7 to 10 days of micafungin, and only patients with growth of yeast or mold in their day-of-transplant cultures received further oral antifungal therapy tailored to their fungal isolate.

Results: IFD events were assessed in sequential cohorts composed of 82 lung transplant recipients before and 83 patients after the implementation of this targeted antifungal strategy. We observed a sharp decline in IFD; in the second cohort, 87%, 91%, and 96% of patients were free of IFD, invasive candidiasis, and invasive aspergillosis at 1 year. Only 19% of patients in the second cohort received systemic antifungal therapy beyond the initial LT hospitalization, and no patients experienced antifungal drug-related toxicity or IFD-associated mortality.

Conclusions: The targeted antifungal strategy studied seems to be a reasonable approach to reducing post-LT IFD events while limiting treatment-related toxicities and costs.
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http://dx.doi.org/10.1097/TP.0b013e318255f864DOI Listing
August 2012

Serum galactomannan and (1->3)-β-D-glucan assays for patients with multiple myeloma and Waldenstrom's macroglobulinemia.

J Clin Microbiol 2012 Mar 14;50(3):1054-6. Epub 2011 Dec 14.

Division of Infectious Diseases, Brigham and Women’s Hospital, Boston, Massachusetts, USA.

We assessed the performance of galactomannan and (1→3)-β-d-glucan in 29 serum samples from patients with multiple myeloma and Waldenstrom's macroglobulinemia without invasive fungal disease to address issues of false positivity and uninterpretable results previously reported among patients with these conditions. Galactomannan and (1→3)-β-d-glucan assays were not falsely elevated in any patient. (1→3)-β-d-glucan assay results were uninterpretable in 24% of patients. Patients with IgG levels of >2,000 mg/dl had higher odds of uninterpretable (1→3)-β-d-glucan results.
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http://dx.doi.org/10.1128/JCM.06295-11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3295114PMC
March 2012

Candida albicans cervical lymphadenitis in patients who have acute myeloid leukemia.

Clin Lymphoma Myeloma Leuk 2011 Aug;11(4):375-7

Division of Infectious Diseases, Brigham and Women's Hospital, Boston, MA, USA.

We describe two patients with acute myelogenous leukemia who developed cervical lymphadenitis and chronic disseminated infection due to Candida albicans. Candida albicans infection should be considered in leukemic patients with acute lymphadenitis. Evaluation for visceral dissemination is warranted even in the absence of fungemia.
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http://dx.doi.org/10.1016/j.clml.2011.06.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4790077PMC
August 2011

Seroprotective titers against 2009 H1N1 influenza A virus after vaccination in allogeneic hematopoietic stem cell transplantation recipients.

Biol Blood Marrow Transplant 2011 Mar 13;17(3):434-8. Epub 2010 Oct 13.

Division of Infectious Diseases, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.

Little data are available regarding the safety and immunologic response to pandemic H1N1 influenza vaccine in recipients of allogeneic hematopoietic stem cell transplantation (HSCT). We measured serum antibody titers against A/California/7/2009 H1N1 using a hemagglutination inhibition assay in 82 allogeneic HSCT recipients who received the 2009 H1N1 vaccine between November 2009 and January 2010 after it became available at our institution. The median time between HSCT and vaccination was 19 months (range, 2.5-94 months), and the median time from vaccination to specimen collection was 56 days (range, 14-140 days). Seroprotective antibody titers (hemagglutination inhibition titer ≥1:40) against 2009 H1N1 influenza A virus were detected in 51% of patients. The presence of chronic graft-versus-host disease and type of conditioning regimen did not affect the rate of detection of seroprotective titers after vaccination. Patients were more likely to have a seroprotective titer the farther away from HSCT they were (adjusted odds ratio, 1.79 per year; 95% confidence interval, 1.12-2.85). Rituximab administration in the year before vaccination was associated with a lack of seroprotective titer (adjusted odds ratio, 0.11; 95% confidence interval, 0.01-0.97). The vaccine was safe and well tolerated. Strategies are needed to improve the influenza vaccine response in this population, especially those receiving immunotherapy.
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http://dx.doi.org/10.1016/j.bbmt.2010.10.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3262168PMC
March 2011

Infection in organ transplantation: risk factors and evolving patterns of infection.

Infect Dis Clin North Am 2010 Jun;24(2):273-83

Transplant Infectious Disease & Compromised Host Program, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, GRJ 504, Boston, MA 02114, USA.

The nature of infections after solid-organ transplantation has changed with increasingly potent immunosuppressive regimens, routine use of antimicrobial prophylaxis, and improved microbiologic diagnostic tools. New pathogens have been identified in this population including many with significant antimicrobial resistance. Intensification of immunosuppressive regimens, including the use of T- and B-lymphocyte depleting agents, presents an increased risk for infection and requires linkage to microbiologic monitoring and prophylaxis against opportunistic infections. The effect of these regimens is reflected in the increased recognition of viral and fungal infections beyond 1 year after transplantation. Donor-derived infections represent a challenge to organ transplantation in terms of microbiologic screening of donors and the need for communication among clinical centers, organ procurement organizations, and public health authorities. New approaches to microbiologic assessment of organ donors and recipients are needed. In the future, improved assays for microbiologic and immunologic monitoring will allow individualization of prophylactic strategies to reduce the risk of infection in this highly susceptible population.
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http://dx.doi.org/10.1016/j.idc.2010.01.005DOI Listing
June 2010

Infectious complications of antilymphocyte therapies in solid organ transplantation.

Clin Infect Dis 2009 Mar;48(6):772-86

Infectious Disease Division, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Antilymphocyte therapies are widely used for immunosuppression in solid organ transplantation. These agents have varied mechanisms of action, with resulting differences in the intensity and duration of immunosuppression and in associated infectious complications. Induction therapy with antithymocyte globulins is associated with a greater incidence of cytomegalovirus, Epstein-Barr virus, and BK polyomavirus infections, compared with therapy with interleukin (IL)-2a receptor antagonists. However, long-term experience with the IL-2a receptor antagonists is lacking. By contrast, the treatment of graft rejection with T cell-depleting antibodies is associated with an increased risk of opportunistic infections. This is likely a reflection of the intensification of immunosuppression in the treatment of graft rejection and, often, a failure to link the use of antilymphocyte agents to prophylaxis for infection. The use of T cell-depleting agents, especially in the treatment of acute graft rejection, must be linked to monitoring and risk-adjusted prophylaxis for Pneumocystis, other fungi, Epstein-Barr virus, BK polyomavirus, and cytomegalovirus infection.
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http://dx.doi.org/10.1086/597089DOI Listing
March 2009

Absence of replication of porcine endogenous retrovirus and porcine lymphotropic herpesvirus type 1 with prolonged pig cell microchimerism after pig-to-baboon xenotransplantation.

J Virol 2008 Dec 1;82(24):12441-8. Epub 2008 Oct 1.

Infectious Disease Division, Massachusetts General Hospital, Boston, Massachusetts, USA.

Porcine endogenous retrovirus (PERV), porcine cytomegalovirus (PCMV), and porcine lymphotropic herpesvirus (PLHV) are common porcine viruses that may be activated with immunosuppression for xenotransplantation. Studies of viral replication or transmission are possible due to prolonged survival of xenografts in baboon recipients from human decay-accelerating factor transgenic or alpha-1,3-galactosyltransferase gene knockout miniature swine. Ten baboons underwent xenotransplantation with transgenic pig organs. Graft survival was 32 to 179 days. Recipient serial samples of peripheral blood mononuclear cells (PBMC) and plasma were analyzed for PCMV, PERV, and PLHV-1 nucleic acids and viral replication using quantitative PCR assays. The PBMC contained PERV proviral DNA in 10 animals, PLHV-1 DNA in 6, and PCMV in 2. PERV RNA was not detected in any PBMC or serum samples. Plasma PLHV-1 DNA was detected in one animal. Pig cell microchimerism (pig major histocompatibility complex class I and pig mitochondrial cytochrome c oxidase subunit II sequences) was present in all recipients with detectable PERV or PLHV-1 (85.5%). Productive infection of PERV or PLHV-1 could not be demonstrated. The PLHV-1 viral load did not increase in serum over time, despite prolonged graft survival and pig cell microchimerism. There was no association of viral loads with the nature of exogenous immune suppression. In conclusion, PERV provirus and PLHV-1 DNA were detected in baboons following porcine xenotransplantation. Viral detection appeared to be due to persistent pig cell microchimerism. There was no evidence of productive infection in recipient baboons for up to 6 months of xenograft function.
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http://dx.doi.org/10.1128/JVI.01278-08DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2593320PMC
December 2008

Sequencing and resolution of amplified herpes simplex virus DNA with intermediate melting curves as genotype 1 or 2 by LightCycler PCR assay.

J Clin Microbiol 2005 Apr;43(4):1843-5

Division of Clinical Microbiology, Mayo Clinic, 200 First St., SW, Rochester, MN 55905, USA.

DNA from 101 specimens containing herpes simplex virus (HSV) produced atypical intermediate melting curves compared with those expected for HSV type 1 or HSV type 2 subsequent to real-time PCR. Nucleic acid sequence analysis of amplified target DNA revealed 1- or 3-bp polymorphisms in the probe region which allowed designation of these viruses as HSV genotype 1 or HSV genotype 2. These two subpopulations of HSV were also identified as HSV genotype 1 or HSV genotype 2 using another commercially available PCR method. Amplified HSV target DNA producing intermediate melting curves could be designated as HSV genotype 1 or HSV genotype 2 without performing sequencing or another PCR method with 96/101 (95%) specimens by adding known intermediate HSV DNA characteristic for the two subpopulations as controls.
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http://dx.doi.org/10.1128/JCM.43.4.1843-1845.2005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1081363PMC
April 2005

In vitro activity of BAL9141 against clinical isolates of gram-negative bacteria.

Diagn Microbiol Infect Dis 2004 Jan;48(1):73-5

Department of Internal Medicine, Rochester, MN, USA.

The minimum inhibitory concentration and minimum bactericidal concentration of BAL9141 against 150 clinical isolates of gram-negative bacteria were determined and compared to those of cefepime and ceftriaxone. BAL9141 exhibited comparable activity to cefepime and ceftriaxone against Haemophilus influenzae, Klebsiella pneumoniae, and extended-spectrum beta-lactamase nonproducing Enterobacter cloacae, and comparable activity to cefepime against Pseudomonas aeruginosa.
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http://dx.doi.org/10.1016/j.diagmicrobio.2003.09.006DOI Listing
January 2004

Potential for expansion of the donor pool using liver allografts from donors with bacterial meningitis.

Liver Transpl 2002 Oct;8(10):977-9

Division of Infectious Diseases, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.

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http://dx.doi.org/10.1053/jlts.2002.0080977DOI Listing
October 2002