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Background Human metapneumovirus (hMPV) epidemiology, clinical characteristics and risk factors for poor outcome after allogeneic stem cell transplantation (allo-HCT) remain a poorly investigated area. Methods This retrospective multicenter cohort study examined the epidemiology, clinical characteristics, and risk factors for poor outcomes associated with human metapneumovirus (hMPV) infections in recipients of allo-HCT. Results We included 428 allo-HCT recipients who developed 438 hMPV infection episodes between January 2012 and January 2019. Most recipients were adults (93%). hMPV infections were diagnosed at a median of 373 days after allo-HCT. The infections were categorized as upper respiratory tract disease (URTD) or lower respiratory tract disease (LRTD), with 60% and 40% of cases, respectively. Patients with hMPV LRTD experienced the infection earlier in the transplant course and had higher rates of lymphopenia, neutropenia, corticosteroid use, and ribavirin therapy. Multivariate analysis identified lymphopenia and corticosteroid use (>30 mg/d) as independent risk factors for LRTD occurrence. The overall mortality at day 30 after hMPV detection was 2% for URTD, 12% for possible LRTD, and 21% for proven LRTD. Lymphopenia was the only independent risk factor associated with day 30 mortality in LRTD cases. Conclusions These findings highlight the significance of lymphopenia and corticosteroid use in the development and severity of hMPV infections after allo-HCT, with lymphopenia being a predictor of higher mortality in LRTD cases. [ABSTRACT FROM AUTHOR]

Background Individuals who receive allogeneic hematopoietic cell transplant (allo-HCT) are immunocompromised and at high risk of pneumococcal infections, especially in the months following transplant. This study evaluated the safety and immunogenicity of V114 (VAXNEUVANCE; Merck, Sharp & Dohme LLC, a subsidiary of Merck & Co. Inc. Rahway, NJ, USA), a 15-valent pneumococcal conjugate vaccine (PCV), when given to allo-HCT recipients. Methods Participants received 3 doses of V114 or PCV13 (Prevnar 13; Wyeth LLC) in 1-month intervals starting 3–6 months after allo-HCT. Twelve months after HCT, participants received either PNEUMOVAX 23 or a fourth dose of PCV (if they experienced chronic graft vs host disease). Safety was evaluated as the proportion of participants with adverse events (AEs). Immunogenicity was evaluated by measuring serotype-specific immunoglobulin G (IgG) geometric mean concentrations (GMCs) and opsonophagocytic activity (OPA) geometric mean titers (GMTs) for all V114 serotypes in each vaccination group. Results A total of 274 participants were enrolled and vaccinated in the study. The proportions of participants with AEs and serious AEs were generally comparable between intervention groups, and the majority of AEs in both groups were of short duration and mild-to-moderate intensity. For both IgG GMCs and OPA GMTs, V114 was generally comparable to PCV13 for the 13 shared serotypes, and higher for serotypes 22F and 33F at day 90. Conclusions V114 was well tolerated in allo-HCT recipients, with a generally comparable safety profile to PCV13. V114 induced comparable immune responses to PCV13 for the 13 shared serotypes, and was higher for V114 serotypes 22F and 33F. Study results support the use of V114 in allo-HCT recipients. Clinical Trials Registration.  clinicaltrials.gov (NCT03565900) and European Union at EudraCT 2018-000066-11. [ABSTRACT FROM AUTHOR]

Background Cytomegalovirus (CMV) infection is a common opportunistic infection after allogeneic hematopoietic cell transplant (alloHCT). We explored whether a change in CMV cell-mediated immunity during the first month after transplant predicts the risk of development of CMV infection and all-cause mortality. Methods This follow-up analysis is based on data from the REACT study, a multicenter prospective observational study of recipients of alloHCT who were CMV-seropositive. Production of interferon γ following ex vivo stimulation with CMV antigens IE1 (immediate early 1) and pp65 (phosphoprotein 65) was assessed by CMV ELISPOT assay at baseline and 2 and 4 weeks after transplant. Clinically significant CMV infection (CS-CMVi) was defined as CMV viremia and/or disease necessitating antiviral therapy. We evaluated the impact of CMV CMI changes on the risk of CS-CMVi and post transplant mortality. Results The analysis included 226 recipients of alloHCT with CMV cell-mediated immunity data at baseline and 2 and/or 4 weeks after transplant. CS-CMVi occurred in 64 patients (28%). On Cox regression analyses, independent predictors of CS-CMVi included a negative Δ change from baseline to week 2 of pp65 spot counts (hazard ratio, 3.65 [95% CI, 1.65–8.04]; P =.001) to week 4 of IE1 spot counts (hazard ratio, 2.79 [95% CI, 1.46–5.35]; P =.002), anti-thymocyte globulin conditioning regimen, type of transplant, female sex, and corticosteroid use. Kaplan-Meir analysis showed a significant association of a negative IE1 change from baseline to week 4 and increased all-cause mortality after transplant (log rank test = 0.041). Conclusions A decrease in CMV-specific T-cell responses during the first month after transplant may predict CS-CMVi and is associated with all-cause mortality in recipients of alloHCT. [ABSTRACT FROM AUTHOR]

Background BK polyomavirus (BKPyV) infection and BK polyomavirus nephropathy (BKPyVAN) are important causes of allograft dysfunction and premature allograft loss in renal transplant recipients. Results and Discussion Controlled clinical trials to evaluate new agents for prevention and treatment are needed but are hampered by the lack of outcome measures that accurately assess the effect of the intervention, are clinically relevant, and are acceptable from a regulatory perspective. Methods To facilitate consistent end points in clinical trials and to support clinical research and drug development, definitions of BKPyV infection and disease have been developed by the BK Disease Definitions Working Group of the Transplantation Associated Virus Infection Forum with the Forum for Collaborative Research, which consists of scientists, clinicians, regulators, and industry representatives. Conclusions These definitions refine established principles of "proven" BKPyV disease and introduce a "probable" disease category that could be used in clinical trials to prevent or treat BKPyVAN in renal transplant recipients. [ABSTRACT FROM AUTHOR]

Background Presatovir significantly reduced nasal viral load, signs, and symptoms of respiratory syncytial virus (RSV) infection in a human challenge study. We evaluated presatovir in hematopoietic-cell transplant (HCT) recipients with RSV lower respiratory tract infection (LRTI). Methods Patients with confirmed RSV in upper and lower respiratory tract and new chest X-ray abnormalities were randomized (1:1), stratified by supplemental oxygen and ribavirin use, to receive oral presatovir 200 mg or placebo every 4 days for 5 doses. The primary endpoint was time-weighted average change in nasal RSV viral load through day 9. Secondary endpoints included supplemental oxygen-free days, incident respiratory failure requiring mechanical ventilation, and all-cause mortality. Results From January 31, 2015, to March 20, 2017, 60 patients from 17 centers were randomized (31 presatovir, 29 placebo); 59 received study treatment (50 allogeneic, 9 autologous HCT). In the efficacy population (29 presatovir, 28 placebo), presatovir treatment did not significantly reduce time-weighted average change in viral load (−1.12 vs −1.09 log10 copies/mL; treatment difference −0.02 log10 copies/mL, 95% confidence interval: −.62,.57; P =.94), median supplemental oxygen-free days (26 vs 28 days, P =.84), incident respiratory failure (10.3 vs 10.7%, P =.98), or all-cause mortality (0 vs 7.1%, P =.19) versus placebo. Adverse events were similar between arms (presatovir 80%, placebo 79%). Resistance-associated substitutions in RSV fusion protein emerged in 6/29 presatovir-treated patients. Conclusions Presatovir treatment was well tolerated in HCT patients with RSV LRTI but did not improve virologic or clinical outcomes versus placebo. Clinical Trials Registration www.clinicaltrials.gov , NCT02254421; EudraCT, #2014-002475-29 [ABSTRACT FROM AUTHOR]

Background Hematopoietic-cell transplant (HCT) recipients are at risk for severe respiratory syncytial virus (RSV) infection. We evaluated the RSV fusion inhibitor presatovir in a randomized, double-blind, Phase II trial in HCT recipients with RSV upper respiratory tract infections. Methods Patients were stratified by lymphopenia (<200/µL) and ribavirin use; were randomized, stratified by lymphopenia (<200/μL) and ribavirin use, to receive oral presatovir at 200 mg or a placebo on Days 1, 5, 9, 13, and 17, and were followed through Day 28. The coprimary efficacy endpoints were the time-weighted average change in the nasal RSV viral load between Days 1 and 9 and the proportion of patients developing lower respiratory tract complications (LRTCs) through Day 28. Results From 23 January 2015 to 16 June 2017, 189 patients were randomly assigned to treatment (96 to presatovir and 93 to the placebo). Presatovir treatment, compared with the placebo treatment, did not significantly affect (prespecified α = 0.01) a time-weighted average decline in the RSV viral load from Day 1 to 9 (treatment difference, −0.33 log10 copies/mL; 95% confidence interval [CI] −.64 to −.02 log10 copies/mL; P =.040) or the progression to LRTC (11.2% vs 19.5%, respectively; odds ratio, 0.50; 95% CI,.22–1.18; P =.11). In a post hoc analysis among patients with lymphopenia, presatovir decreased LRTC development by Day 28 (2/15 [13.3%] vs 9/14 [64.3%], respectively; P =.008), compared with the placebo. Adverse events were similar for patients receiving presatovir and the placebo. Conclusions Presatovir had a favorable safety profile in adult HCT recipients with RSV but did not achieve the coprimary endpoints. Exploratory analyses suggest an antiviral effect among patients with lymphopenia. Clinical Trials Registration NCT02254408; EUDRA-CT#2014-002474-36. [ABSTRACT FROM AUTHOR]

Background Cytomegalovirus (CMV) infection remains an important cause of morbidity and mortality in allogeneic hematopoietic cell transplant (allo-HCT) recipients. CMV cell-mediated immunity (CMV-CMI) as determined by a peptide-based enzyme-linked immunospot (ELISPOT) CMV assay may identify patients at risk for clinically significant CMV infection (CS-CMVi). Methods The CS-CMVi was defined as CMV viremia and/or disease necessitating antiviral therapy. CMV-CMI was characterized as high when the intermediate-early 1 (IE-1) antigen spot counts (SPCs) were >100 (cutoff 1) or when the IE-1 and phosphoprotein 65 antigen SPCs were both >100 SPCs per 250 000 cells (cutoff 2), and a low CMV-CMI when SPCs were below these thresholds. In this prospective multicenter study, we evaluated CMV-CMI every 2 weeks from the pretransplant period until 6 months posttransplantation in 241 allo-HCT recipients with positive CMV serostatus. The primary endpoint was CS-CMVi occurring within 2 weeks of the last measurement of CMV-CMI. Results CS-CMVi occurred in 70 allo-HCT recipients (29%). CMV-CMI was low in patients who experienced CS-CMVi (94%), whereas those who had a high CMV-CMI were less likely to have CS-CMVi (P  < .0001). Patients with CS-CMVi had higher all-cause mortality (P  = .007), especially those with low CMV-CMI (P  = .035). On multivariable analysis, CMV-CMI, sex, race, antithymocyte globulin, and steroid use were independent predictors of CS-CMVi, and the time from transplant to engraftment was the only predictor of mortality. Conclusions Measurement of CMV-CMI using a novel ELISPOT assay would be useful clinically to monitor allo-HCT recipients and distinguish between those at risk of developing CS-CMVi and requiring antiviral prophylaxis or therapy and those who are protected. [ABSTRACT FROM AUTHOR]

Background In a phase 3 trial, letermovir reduced clinically significant cytomegalovirus infections (CS-CMVi) and all-cause mortality at week 24 versus placebo in CMV-seropositive allogeneic hematopoietic cell transplantation (HCT) recipients. This post hoc analysis of phase 3 data further investigated the effects of letermovir on all-cause mortality. Methods Kaplan-Meier survival curves were generated by treatment group for all-cause mortality. Observations were censored at trial discontinuation for reasons other than death or at trial completion. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox modeling, adjusting for risk factors associated with mortality. Results Of 495 patients with no detectable CMV DNA at randomization, 437 had vital-status data available through week 48 post-HCT at trial completion (101 deaths, 20.4%). Following letermovir prophylaxis, the HR for all-cause mortality was 0.58 (95% CI, 0.35–0.98; P =.04) at week 24 and 0.74 (95% CI, 0.49–1.11; P =.14) at week 48 post-HCT versus placebo. Incidence of all-cause mortality through week 48 post-HCT in the letermovir group was similar in patients with or without CS-CMVi (15.8 vs 19.4%; P =.71). However, in the placebo group, all-cause mortality at week 48 post-HCT was higher in patients with versus those without CS-CMVi (31.0% vs 18.2%; P =.02). The HR for all-cause mortality in patients with CS-CMVi was 0.45 (95% CI, 0.21–1.00; P =.05) at week 48 for letermovir versus placebo. Conclusions Letermovir may reduce mortality by preventing or delaying CS-CMVi in HCT recipients. Clinical Trials Registration clinicaltrials.gov, NCT02137772. [ABSTRACT FROM AUTHOR]

Despite advances in preventive strategies, cytomegalovirus (CMV) infection remains a major complication in solid organ and hematopoietic cell transplant recipients. CMV infection may fail to respond to commercially available antiviral therapies, with or without demonstrating genotypic mutation(s) known to be associated with resistance to these therapies. This lack of response has been termed "resistant/refractory CMV" and is a key focus of clinical trials of some investigational antiviral agents. To provide consistent criteria for future clinical trials and outcomes research, the CMV Resistance Working Group of the CMV Drug Development Forum (consisting of scientists, clinicians, regulatory officials, and industry representatives from the United States, Canada, and Europe) has undertaken establishing standardized consensus definitions of "resistant" and "refractory" CMV. These definitions have emerged from the Working Group's review of the available virologic and clinical literature and will be subject to reassessment and modification based on results of future studies. [ABSTRACT FROM AUTHOR]

The European Conference on Infections in Leukaemia (ECIL) updated its guidelines on antifungal prophylaxis for adults using the grading system of IDSA. The guidelines were extended to provide recommendations for other haematological diseases besides AML and recipients of an allogeneic haematopoietic stem cell transplantation (HSCT). Posaconazole remains the drug of choice when the incidence of invasive mould diseases exceeds 8%. For patients undergoing remission-induction chemotherapy for AML and myelodysplastic syndrome (MDS), fluconazole can still offer an alternative provided it forms part of an integrated care strategy that includes screening with biomarkers and imaging. Similarly, aerosolized liposomal amphotericin B combined with fluconazole can be considered for patients at high risk of invasive mould diseases but other formulations of the polyene are discouraged. Fluconazole is still recommended as primary prophylaxis for patients at low risk of invasive mould diseases during the pre-engraftment phase of allogeneic HSCT whereas only a moderate recommendation could be made for itraconazole, posaconazole and voriconazole for patients at high risk. Posaconazole is strongly recommended for preventing invasive mould disease post-engraftment but only when graft-versus-host disease (GvHD) was accompanied by other risk factors such as its severity, use of an alternative donor or when unresponsive to standard corticosteroid therapy. The need for primary prophylaxis for other patient groups was less clear and should be defined by the estimated risk of invasive fungal disease (IFD). [ABSTRACT FROM AUTHOR]

Background This study was performed to assess the incidence of and risk factors for Candida infection in the first 100 days after allogeneic hematopoietic stem cell transplantation (HSCT) and the impact on long-term survival. Methods We performed an outcome analysis of 28542 acute leukemia patients who underwent HSCT from 2000 to 2012. There were 347 patients with candidemia by day 100 and 28195 without candidemia or any other type of Candida infection. Results The incidence of candidemia by day 100 was 1.2% and occurred at a median of 22 days after HSCT. Higher 100-day nonrelapse mortality (NRM; hazards ratio [HR], 3.0, P <.0001) and lower 100-day overall survival (OS; HR, 2.5, P <.0001) were observed in patients with candidemia. The case fatality rate by day 100 in patients with candidemia was 22% (76/347). Factors associated with candidemia occurrence were female gender, bone marrow or cord blood stem cell source, T-cell depletion, use of total body irradiation, and acute graft vs host disease. Among the patients alive at day 100, the 5-year NRM and OS after a median follow-up of 5.6 years (95% confidence interval, 5.5 – 5.7) for patients with and without candidemia were 22.5% vs 13.5%, P <.0001 and 45.6% vs. 53.4%, P =.0003, respectively. In multivariate analysis, the occurrence of a candidemia episode by day 100 was an independent risk factor for higher NRM (HR, 1.7, P =.001) and lower OS (HR, 1.4, P =.001). Conclusions The early occurrence of candidemia after HSCT is still associated with higher NRM and lower short- and-long-term OS. [ABSTRACT FROM AUTHOR]

Symptomatic cytomegalovirus (CMV) disease has been the standard endpoint for clinical trials in organ transplant recipients. Viral load may be a more relevant endpoint due to low frequency of disease. We performed a meta-analysis and systematic review of the literature. We found several lines of evidence to support the validity of viral load as an appropriate surrogate end-point, including the following: (1) viral loads in CMV disease are significantly greater than in asymptomatic viremia (odds ratio, 9.3 95% confidence interval, 4.6-19.3); (2) kinetics of viral replication are strongly associated with progression to disease; (3) pooled incidence of CMV viremia and disease is significantly lower during prophylaxis compared with the full patient follow-up period (viremia incidence: 3.2% vs 34.3%; P < .001) (disease incidence: 1.1% vs 13.0%; P < .001); (4) treatment of viremia prevented disease; and (5) viral load decline correlated with symptom resolution. Based on the analysis, we conclude that CMV load is an appropriate surrogate endpoint for CMV trials in organ transplant recipients. [ABSTRACT FROM AUTHOR]

Background. This intercontinental study aimed to study gram-negative rod (GNR) resistance in hematopoietic stem cell transplantation (HSCT). Methods. GNR bacteremias occurring during 6 months post-HSCT (February 2014-May 2015) were prospectively collected, and analyzed for rates and risk factors for resistance to fluoroquinolones, noncarbapenem anti-Pseudomonas β-lactams (noncarbapenems), carbapenems, and multidrug resistance. Results. Sixty-five HSCT centers from 25 countries in Europe, Australia, and Asia reported data on 655 GNR episodes and 704 pathogens in 591 patients (Enterobacteriaceae, 73%; nonfermentative rods, 24%; and 3% others). Half of GNRs were fluoroquinolone and noncarbapenem resistant; 18.5% carbapenem resistant; 35.2% multidrug resistant. The total resistance rates were higher in allogeneic HSCT (allo-HSCT) vs autologous HSCT (auto-HSCT) patients (P < .001) but similar in community-acquired infections. Noncarbapenem resistance and multidrug resistance were higher in auto-HSCT patients in centers providing vs not providing fluoroquinolone prophylaxis (P < .01). Resistance rates were higher in southeast vs northwest Europe and similar in children and adults, excluding higher fluoroquinolone- and β-lactam/β-lactamase inhibitor resistance rates in allo-HSCT adults. Non-Klebsiella Enterobacteriaceae were rarely carbapenem resistant. Multivariable analysis revealed resistance risk factors in allo-HSCT patients: fluoroquinolone resistance: adult, prolonged neutropenia, breakthrough on fluoroquinolones; noncarbapenem resistance: hospital-acquired infection, breakthrough on noncarbapenems or other antibiotics (excluding fluoroquinolones, noncarbapenems, carbapenems), donor type; carbapenem resistance: breakthrough on carbapenem, longer hospitalization, intensive care unit, previous other antibiotic therapy; multidrug resistance: longer hospitalization, breakthrough on β-lactam/β-lactamase inhibitors, and carbapenems. Inappropriate empiric therapy and mortality were significantly more common in infections caused by resistant bacteria. Conclusions. Our data question the recommendation for fluoroquinolone prophylaxis and call for reassessment of local empiric antibiotic protocols. Knowledge of pathogen-specific resistance enables early appropriate empiric therapy. Monitoring of resistance is crucial. Clinical Trials Registration. NCT02257931 [ABSTRACT FROM AUTHOR]

Cytomegalovirus (CMV) infection and disease are important causes of morbidity and mortality in transplant recipients. For the purpose of developing consistent reporting of CMV outcomes in clinical trials, definitions of CMV infection and disease were developed and most recently published in 2002. Since then, there have been major developments in its diagnosis and management. Therefore, the CMV Drug Development Forum consisting of scientists, clinicians, regulators, and industry representatives has produced an updated version incorporating recent knowledge with the aimto support clinical research and drug development. The main changes compared to previous definitions are the introduction of a "probable disease" category and to incorporate quantitative nucleic acid testing in some end-organ disease categories. As the field evolves, the need for updates of these definitions is clear, and collaborative efforts between scientists, regulators, and industry can provide a platform for this work. [ABSTRACT FROM AUTHOR]

Background. Life-threatening Streptococcus pneumoniae infections often occur after hematopoietic stem cell transplant (HSCT); vaccination is important for prevention. Methods. In an open-label study, patients (n = 251) 3-6 months after allogeneic HSCT received 3 doses of 13-valent pneumococcal conjugate vaccine (PCV13) at 1-month intervals, a fourth dose 6 months later, and 1 dose of 23-valent pneumococcal polysaccharide vaccine (PPSV23) 1 month later. Immunogenicity at prespecified time points and vaccine safety were assessed. Results. In the evaluable immunogenicity population (N = 216; mean age, 37.8 years), geometric mean fold rises (GMFRs) of immunoglobulin G geometric mean concentrations from baseline to postdose 3 showed significant increases in antibody levels across all PCV13 serotypes (GMFR range, 2.99-23.85; 95% confidence interval lower limit, >1); there were significant declines over the next 6 months, significant increases from predose 4 to postdose 4 (GMFR range, 3.00-6.97), and little change after PPSV23 (GMFR range, 0.86-1.12). Local and systemic reactions were more frequent after dose 4. Six patients experienced serious adverse events possibly related to PCV13 (facial diplegia, injection-site erythema and pyrexia, autoimmune hemolytic anemia, and suspected lack of vaccine efficacy after dose 3 leading to pneumococcal infection), PCV13 and PPSV23 (Guillain-Barré syndrome), or PPSV23 (cellulitis). There were 14 deaths, none related to study vaccines. Conclusions. A 3-dose PCV13 regimen followed by a booster dose may be required to protect against pneumococcal disease in HSCT recipients. Dose 4 was associated with increased local and systemic reactions, but the overall safety profile of a 4-dose regimen was considered acceptable. [ABSTRACT FROM AUTHOR]

The use of a cytomegalovirus (CMV)–seropositive unrelated hematopoietic stem cell transplant (HSCT) donor for a CMV-seronegative patient results in reduced overall survival. The use of a CMV-seronegative unrelated HSCT donor for a seropositive patient results in reduced overall survival after myeloablative conditioning.Background. The use of a cytomegalovirus (CMV)–seronegative donor for a CMV-seronegative allogeneic hematopoietic stem cell transplant (HSCT) recipient is generally accepted. However, the importance of donor serostatus in CMV-seropositive patients is controversial.Methods. A total of 49 542 HSCT patients, 29 349 seropositive and 20 193 seronegative, were identified from the European Group for Blood and Marrow Transplantation database. Cox multivariate models were fitted to estimate the effect of donor CMV serological status on outcome.Results. Seronegative patients receiving seropositive unrelated-donor grafts had decreased overall survival (hazard ratio [HR], 1.13; 95% confidence interval [CI], 1.06–1.21; P < .0001) compared with seronegative donors, whereas no difference was seen in patients receiving HLA-matched sibling grafts. Seropositive patients receiving grafts from seropositive unrelated donors had improved overall survival (HR, 0.92; 95% CI, .86–.98; P < .01) compared with seronegative donors, if they had received myeloablative conditioning. This effect was absent when they received reduced-intensity conditioning. No effect was seen in patients grafted from HLA-identical sibling donors. The same association was found if the study was limited to patients receiving transplants from the year 2000 onward.Conclusions. We confirm the negative impact on overall survival if a CMV-seropositive unrelated donor is selected for a CMV-seronegative patient. For a CMV-seropositive patient, our data support selecting a CMV-seropositive donor if the patient receives a myeloablative conditioning regimen. [ABSTRACT FROM PUBLISHER]

An international panel of experts prepared an evidenced-based guideline for vaccination of immunocompromised adults and children. These guidelines are intended for use by primary care and subspecialty providers who care for immunocompromised patients. Evidence was often limited. Areas that warrant future investigation are highlighted. [ABSTRACT FROM PUBLISHER]

More than two-thirds of patients with Epstein-Barr virus–related posttransplant lymphoproliferative disorder after hematopoietic stem cell transplant can be cured with rituximab-based treatment. Reduction of immunosuppression is associated with improved outcome; older age, extranodal disease, and acute graft-vs-host disease predict poor outcome.Background. The objective of this analysis was to investigate prognostic factors that influence the outcome of Epstein-Barr virus (EBV)–related posttransplant lymphoproliferative disorder (PTLD) after a rituximab-based treatment in the allogeneic hematopoietic stem cell transplant (HSCT) setting.Methods. A total of 4466 allogeneic HSCTs performed between 1999 and 2011 in 19 European Group for Blood and Marrow Transplantation centers were retrospectively analyzed for PTLD, either biopsy-proven or probable disease.Results. One hundred forty-four cases of PTLD were identified, indicating an overall EBV-related PTLD frequency of 3.22%, ranging from 1.16% for matched-family donor, 2.86% for mismatched family donor, 3.97% in matched unrelated donors, and 11.24% in mismatched unrelated donor recipients. In total, 69.4% patients survived PTLD. Multivariable analysis showed that a poor response of PTLD to rituximab was associated with an age ≥30 years, involvement of extralymphoid tissue, acute GVHD, and a lack of reduction of immunosuppression upon PTLD diagnosis. In the prognostic model, the PTLD mortality increased with the increasing number of factors: 0–1, 2, or 3 factors being associated with mortality of 7%, 37%, and 72%, respectively (P < .0001). Immunosuppression tapering was associated with a lower PTLD mortality (16% vs 39%), and a decrease of EBV DNAemia in peripheral blood during therapy was predictive of better survival.Conclusions. More than two-thirds of patients with EBV-related PTLD survived after rituximab-based treatment. Reduction of immunosuppression was associated with improved outcome, whereas older age, extranodal disease, and acute graft-vs-host disease predicted poor outcome. [ABSTRACT FROM PUBLISHER]

Respiratory viruses have been recognized as a significant cause of morbidity and mortality in patients with leukemia and those undergoing hematopoietic stem cell transplantation. The risk for lower respiratory tract infections and a fatal outcome appears to depend on the intrinsic virulence of the specific community-acquired respiratory virus as well as factors specific to the patient, the underlying disease, and its treatment.Community-acquired respiratory virus (CARV) infections have been recognized as a significant cause of morbidity and mortality in patients with leukemia and those undergoing hematopoietic stem cell transplantation (HSCT). Progression to lower respiratory tract infection with clinical and radiological signs of pneumonia and respiratory failure appears to depend on the intrinsic virulence of the specific CARV as well as factors specific to the patient, the underlying disease, and its treatment. To better define the current state of knowledge of CARVs in leukemia and HSCT patients, and to improve CARV diagnosis and management, a working group of the Fourth European Conference on Infections in Leukaemia (ECIL-4) 2011 reviewed the literature on CARVs, graded the available quality of evidence, and made recommendations according to the Infectious Diseases Society of America grading system. Owing to differences in screening, clinical presentation, and therapy for influenza and adenovirus, ECIL-4 recommendations are summarized for CARVs other than influenza and adenovirus. [ABSTRACT FROM PUBLISHER]

Using positive selection with HLA multimers and magnetic beads, we isolated cytotoxic T lymphocytes from both frozen donor material as well as third-party donors within hours. In addition, we successfully treated 8 patients suffering from severe viral infections after allogeneic hematopoietic stem cell transplantation.Background. Viral infections are major complications after allogeneic hematopoietic stem cell transplantation (HSCT). During posttransplant immunosuppression the regular T-cell control is compromised. Even if treatment strategies against infections caused by herpes viruses such as cytomegalovirus, Epstein-Barr virus, and adenovirus have improved, the mortality rate is still considerable. If primary antiviral therapy fails or cannot be tolerated, adoptive therapy with virus-specific cytotoxic T cells (CTL) can be utilized.Methods. In this study, we used virus-specific CTLs to treat 8 patients suffering from severe viral infections after allogeneic HSCT. Using positive selection with HLA multimers and magnetic beads, we isolated CTLs from both frozen donor material as well as third-party donors within hours.Results. At 90 days after CTL infusions 7 out of 8 patients were still living. CTLs infused from third-party donors were detected in 5 of 6 patients up to 76 days after infusion. No graft-versus-host disease associated with CTL infusions was observed.Conclusions. Our separation approach offers a rapid alternative for adoptive CTL therapy if primary antiviral treatment strategies fail. Because no prolonged expansion steps are needed, this method may be used for early treatment of patients suffering from life-threatening infectious complications. [ABSTRACT FROM AUTHOR]

Background. Invasive pneumococcal disease is a life-threatening complication after allogeneic stem cell transplantation, and at least 20% of cases occur within 1 year after transplantation. The 23-valent pneumococcal polysaccharide vaccine (PPV23) has limited efficacy, especially during the first year after transplantation. The immune response to the conjugated vaccines is expected to be better than that to the polysaccharide vaccine, but the optimal timing of vaccination is not defined. Our objective was to show that a 7-valent pneumococcal conjugate vaccine (PCV7; Prevnar) was not inferior when first given 3 months after transplantation, compared with when first given 9 months after transplantation. Methods. We performed a multicenter, randomized, noninferiority study involving 158 patients from 13 European Group for Blood and Marrow Transplantation centers who were randomly allocated at ∼100 days after myeloablative stem cell transplantation to receive a series of vaccinations (3 doses of PCV7 given 1 month apart) that was started immediately (i.e., 3 months after transplantation) or 6 months later (i.e., 9 months after transplantation). The primary evaluation criterion was the rate of response (antibody level, ⩾0.15 mg/μL for each of the 7 serotypes) at 1 month after the third dose of PCV7. The noninferiority margin was 20%. All patients were followed up for 24 months after transplantation or until death, whichever occurred first. Results. We found that the response rate was not lower after early vaccination (79% [45 of 57 patients]) than after late vaccination (82% [47 of 57 patients]) (difference, -3.5%; 90% confidence interval, -15.6 to 8.6; not significant). Conclusions. We conclude that PCV7 vaccination at 3 months after stem cell transplantation is not inferior to PCV7 vaccination at 9 months after transplantation. Because invasive pneumococcal disease can occur early, we recommend starting the PCV7 vaccination series at 3 months after transplantation to ensure earlier protection against Streptococcus pneumoniae. However, the early vaccination may result in only short-lasting response and may not prime for a 23-valent pneumococcal polysaccharide vaccine boost as efficiently as the late vaccination. [ABSTRACT FROM AUTHOR]

Cytomegalovirus (CMV) has major consequences after allogeneic stem cell and solid organ transplantation. CMV may cause significant morbidity and mortality, and monitoring to detect reactivation to reduce disease or management of end organ disease is associated with increased resource utilization. Two other members of the β-herpesvirus family, human herpesvirus (HHV) type 6 and HHV-7, are increasingly recognized as important pathogens in transplant recipients, either by direct infection (e.g., encephalitis, hepatitis, or pneumonitis) or via interaction with CMV. In addition to direct effects of CMV infection, such indirect effects as an increased risk for bacterial and fungal infections or impaired graft acceptance and function are important research topics. Diagnosis and treatment of CMV infection is currently more advanced than for HHV-6 and HHV-7. [ABSTRACT FROM AUTHOR]

Cytomegalovirus (CMV) infection and disease are important causes of morbidity and mortality among transplant recipients. For the purpose of developing consistent reporting of CMV in clinical trials, definitions of CMV infection and disease were developed and published. This study seeks to update the definitions of CMV on the basis of recent developments in diagnostic techniques, as well as to add to these definitions the concept of indirect effects caused by CMV. [ABSTRACT FROM AUTHOR]

Presents pretransplant strategies for preventing infections after solid-organ transplantation. Pretransplant infections which pose potential risks to all organ transplant groups; Vaccines recommended for patients who will undergo transplantation; Management of fungal infections.

Examines effect of granulocyte-macrophage colony-stimulating factor on the serological response at influenza vaccination in patients who had undergone stem cell transplantation. Increase in level of influenza hemagglutination-inhibition antibodies; Activation of antigen-presenting cells.

Assays cerebrospinal fluid specimens from allogeneic bone marrow transplant patients with central nervous system (CNS) symptoms and patients without CNS symptoms who were immunocompromised for human herpesvirus 6 (HHV-6) DNA. Identification of HHV-6 variant B; Occurrence of HHV-6-associated CNS disease after bone marrow transplantation; Treatment of the disease with ganciclovir or foscarnet.

Immunocompromised patients with influenza A were identified in Stockholm during two influenza seasons. The predominant subtypes were H3N2 during 1988–1989 and H1N1 during 1990–1991. The median age of the 25 patients was 43 years (range, 3–80 years). Twelve patients had received renal transplants and had ongoing immunosuppression. Seven patients had received bone marrow transplants between 2 days and 3 years before becoming infected with influenza virus A. Two patients were in an aplastic phase, and four had chronic graft-versus-host disease with ongoing immunosuppression. Six patients had hematologic malignancies. Two of the 25 patients had severe infections. One of these infections occurred in a bone marrow transplant recipient during an aplastic phase and was fatal; the other affected a patient who had received a renal transplant. One bone marrow transplant patient had mild but protracted infection. The remaining 22 patients had mild influenza A. We conclude that influenza A in immunocompromised patients occasionally causes severe complications but in most patients is mild and self-limiting. [ABSTRACT FROM PUBLISHER]

An ELISA was used to study long-term immunity and immunization responses to tetanus toxoid in 48 bone marrow transplant recipients. Among patients who were seropositive to tetanus before transplant, 51% had lost their seropositivity 1 year later. All patients who were not reimmunized with tetanus toxoid were seronegative 2 years after transplant. All patients who were seronegative before transplant remained seronegative 1 year later regardless of the donor's serologic status. There was no difference in the ability to remain seropositive to tetanus toxoid between patients with and without chronic graft-versus-host disease. Of 21 patients immunized with one dose oftetanus toxoid 1 year after transplant, 14 were seronegative at the time ofimmunization (response rate, 64%). At 1 year after immunization, 7 remained seropositive. Ten patients were reimmunized with two doses of tetanus toxoid. All responded and 90% remained seropositive 1 year later. When 21 patients were primarily immunized with three doses oftetanus toxoid, all patients seronegative at immunization responded and all tested patients remained seropositive 2 years later. The immunization responses were significantly superior in patients receiving three doses compared with those who received one. Reimmunization with tetanus toxoid oflong-term survivors after marrow transplant seems necessary. A three-dose immunization schedule is recommended to obtain an adequate immune response. [ABSTRACT FROM PUBLISHER]

Cytomegalovirus (CMV) viremia and excretion from the oropharynx and urine were examined for their utility in predicting the development of CMV disease, including pneumonia and gastrointestinal disease, among 617 marrow allograft recipients. CMV viremia had a 60% and excretion from oropharynx or urine or viremia a 44% positive predictive value for the development ofCMV disease. Viremia or excretion preceded disease onset by a median of 15 days among those in whom excretion occurred first. In stepwise time-dependent proportional hazards regression analyses, CMV viremia and positive serology before transplant were predictive for both CMV pneumonia and gastrointestinal disease. Oropharyngeal excretion was independently predictive for gastrointestinal disease but not pneumonia. Urinary excretion was not independently predictive. Acute graft-versus-host disease was predictive for pneumonia but not gastrointestinal disease. Thus use ofCMV excretion, particularly viremia, as a marker to determine the initiation ofantiviral chemotherapy could be effective in preventing progression of infection to serious disease. However, with standard virologic techniques this strategy would not be effective in patients (32% in this study) without CMV excretion detected before the onset of pneumonia or gastrointestinal disease. [ABSTRACT FROM PUBLISHER]

Three marrow transplant patients developed pneumonia due to acyclovir-resistant thymidinekinase- deficient herpes simplexvirus (HSV) type 1. In all three, pneumonia was evident at autopsy by both standard and immunohistology, and virus was recovered from culture of lung tissue. Two patients also had other pulmonary infections at death; one had only HSV pneumonia. All had received prophylaxis and repeated treatment courses with acyclovir, and all initially had acyclovir-sensitive virus. The acyclovir-resistant HSV strains were sensitive to foscarnet, and in at least one case to vidarabine, but as expected were resistant to ganciclovir. These cases represent potentially severe visceral infection in which acyclovir-resistant virus strains were primary or important copathogens. Although acyclovir-resistant HSV is generally considered less virulent, these cases illustrate the potential importance of infection due to acyclovir-resistant HSV in severely immunocompromised patients. They also highlight the need to test HSV strains for antiviral sensitivity and to consider alternative therapies to acyclovir in appropriate clinical situations. [ABSTRACT FROM PUBLISHER]

The frequencies of reactivated disease due to varicella-zoster virus (VZV) in immunocompromised patients were determined by enzyme-linked immunosorbent assay for antibody and also by the lymphocyte proliferation response to VZV antigen. Subclinical reactivations were as common as classical herpes zoster in all patient groups. Among bone marrow transplant (BMT) recipients, 36% developed herpes zoster and 26%, a subclinical reactivation. The corresponding frequencies for patients with leukemia during induction therapy were 5% and 10%; in renal transplant recipients, 0% and 26%; and in patients with seminoma, 0% and 6%, respectively. Subclinical reactivation of VZV thus appears to be a common finding in severely immunocompromised patients. A regained lymphocyte proliferation response to VZV antigen is a sensitive indicator of subclinical reactivation of VZV in BMT recipients. None of 19 BMT recipients with subclinical disease due to VZV later developed clinical reactivation of VZV. Acyclovirgiven as prophylaxis against infection with herpes simplex virus reduced the number of clinical and subclinical reactivations of VZV during treatment in BMT recipients, but not thereafter. [ABSTRACT FROM PUBLISHER]

Antiviral humoral reactivity was studied after bone marrow transplantation. Antiviral IgG — reflecting the presence of functional B cells — was found for a substantial period after transplantation. However, most patients unexpectedly stopped producing antibody after an extended period of observation (i.e., for more than three months and up to as long as 12 months). This cessation was noted whether the viral reactivity involved was of donor or recipient origin. The transferred viral antibody-producing cells thus usually persisted for only a moderate length of time and seemed to have a finite life span. The findings indicate that donor and recipient memory cells are susceptible to the conditioning regimen or to the treatment that follows transplantation. In a few cases transferred immunity of long duration was seen; this finding indicated the occasional engraftment of memory cells. [ABSTRACT FROM PUBLISHER]

In this article, the author discusses effects of Respiratory syncytial virus (RSV) in hematopoietic stem cell transplant recipients and the factors that determine the progress of RSV in the patients suffering from chronic obstructive pulmonary disease (COPD). Topics discussed include effect of RSV therapy with ribavirin, effect of specific humoral immunity on RSV outcomes, and lower risk of poor outcomes of RSV infection in autologous HSCT recipients.