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The acquisition or reactivation of Epstein-Barr virus (EBV) after allogeneic Hematopoietic Stem Cell Transplant (HSCT) can be associated with complications including the development of post-transplant lymphoproliferative disorder (PTLD), which is associated with significant morbidity and mortality. A number of risk factors for PTLD have been defined, including T-cell depletion, and approaches to monitoring EBV, especially in high-risk patients, with the use of preemptive therapy upon viral activation have been described. Newer therapies for the preemption or treatment of PTLD, such as EBV-specific cytotoxic T-cells, hold promise. Further studies to help define risks, diagnosis, and treatment of EBV-related complications are needed in this at-risk population.

PurposeThe aim of this study was to assess the cost effectiveness of letermovir prophylaxis with the option for subsequent pre-emptive therapy (PET) for the prevention of cytomegalovirus (CMV) infection compared with a PET-only scenario in adult allogeneic hematopoietic stem cell transplant (allo-HCT) recipients in the United States over a 10-year time horizon.Materials and methodsA publicly available decision tree model was constructed using a commercial third-party payer perspective to simulate an allo-HCT recipient's clinical trajectory in the first-year post-transplant, followed by entry to a Markov model to simulate years 2 through 10. Clinical inputs and utility estimates were derived from published literature. Costs were derived from published literature and US Department of Veterans Affairs Federal Supply Schedule drug pricing. Outcomes assessed included life expectancy, quality-adjusted life-years (QALYs), direct medical costs, and the incremental cost-effectiveness ratio (ICER). One-way and probabilistic sensitivity analyses (PSA) were performed to test the robustness of the findings.ResultsCompared with PET alone, letermovir prophylaxis was projected to increase life-years per person (4.99 vs. 4.70 life-years), and increase QALYs (3.29 vs. 3.08) and costs (US$83.411 vs. US$70,698), yielding an ICER of US$59,356 per QALY gained. One-way sensitivity analyses indicated our model was sensitive to mortality (ICER: $164,771/QALY) and utility (letermovir ICER: $117,447/QALY; PET ICER: $107,290/QALY) in the first-year post-transplant. In 57.1% of the PSA simulations, letermovir was a cost-effective option using a willingness-to-pay threshold of US$100,000 per QALY.ConclusionsLetermovir prophylaxis is cost effective compared with PET alone with a willingness-to-pay threshold of US$100,000 per QALY gained. Sensitivity analysis results indicate future research is required to understand the impact of mortality and quality of life in the first-year post-transplant to arrive at a conclusive decision on letermovir adoption.

The use of post-transplantation cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis in recipients of haploidentical and fully matched transplantations is on the increase. Published studies have reported an increased incidence of cytomegalovirus (CMV) infection with the use of PTCy. Limited data exist on the incidence and outcomes of infection with non-CMV herpesviruses (NCHV) in this setting. The aim of this study was to evaluate the cumulative incidence of NCHV infections and the association of NCHV infections with transplantation-specific outcomes in recipients of haploidentical transplantation with PTCy (HaploCy), matched sibling donor transplantation with PTCy (SibCy), and matched sibling donor transplantation with calcineurin inhibitor-based prophylaxis (SibCNI). We hypothesized that, like CMV infection, HaploCy recipients of also will have a higher risk of NCHV infections. Using the Center for International Blood and Marrow Transplantation Research database, we analyzed 2765 patients (HaploCy, n = 757; SibCNI, n = 1605; SibCy, n = 403) who had undergone their first hematopoietic stem cell transplantation (HCT) between 2012 and 2017 for acute myelogenous leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome. The cumulative incidence of NCHV at 6 months post-NCT was 13.9% (99% confidence interval], 10.8% to 17.3%) in the HaploCy group, 10.7% (99% CI, 7.1% to 15%) in the SibCy group, and 5.7% (99% CI, 4.3% to 7.3%) in the Sib CNI group (P < .001). This was due primarily to a higher frequency of human herpesvirus 6 viremia reported in patients receiving PTCy. The incidence of Epstein-Barr viremia was low in all groups, and no cases of post-transplantation lymphoproliferative disorder were seen in either PTCy group. The incidence of NCHV organ disease was low in all 3 cohorts. The development of NCHV infection was associated with increased treatment-related mortality, particularly in the HaploCy group. There was no association with the development of GVHD, relapse, or disease-free survival. Patients in PTCy cohorts who did not develop NCHV infection had lower rates of cGVHD. This study demonstrates that the use of PTCy is associated with an increased risk of NCHV infection. The development of NCHV infection was associated with increased nonrelapse mortality, especially in the HaploCy group. Prospective trials should consider viral surveillance strategies in conjunction with assessment of immune reconstitution for a better understanding of the clinical relevance of viral reactivation in different HCT settings.

Community respiratory viral infections (CRVIs) are associated with pulmonary function impairment, alloimmune lung syndromes and inferior survival in human leucocyte antigen (HLA)-matched allogeneic haematopoietic stem cell transplant (HCT) recipients. Although the incidence of viral infections in HLA-haploidentical HCT recipients who receive post-transplant cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis is reportedly increased, there are insufficient data describing the incidence of CRVIs and the impact of donor source and PTCy on transplant outcomes. Analysing patients receiving their first HCT between 2012 and 2017 for acute myeloid leukaemia, acute lymphoblastic leukaemia and myelodysplastic syndromes, we describe comparative outcomes between matched sibling transplants receiving either calcineurin-based GVHD prophylaxis (SibCNI, N = 1605) or PTCy (SibCy, N = 403), and related haploidentical transplants receiving PTCy (HaploCy, N = 757). The incidence of CRVIs was higher for patients receiving PTCy, regardless of donor type. Patients in the HaploCy cohort who developed a CRVI by day +180 had both a higher risk of treatment-related mortality [hazard ratio (HR) 2⋅14, 99% confidence interval (CI) 1⋅13-4⋅07; P = 0⋅002] and inferior 2-year overall survival (HR 1⋅65, 99% CI 1⋅11-2⋅43; P = 0⋅001) compared to SibCNI with no CRVI. This finding justifies further research into long-term antiviral immune recovery, as well as development of preventive and treatment strategies to improve long-term outcomes in such patients.

Abstract Background As of June 2, 2020, 67,113 cases and 321 deaths due to Coronavirus Disease 19 (COVID-19) have been reported in healthcare personnel (HCP) in the United States. Given the close contact of HCP with individuals with COVID-19, it is important to quantify the risk of acquiring COVID-19 in the healthcare setting. Methods We conducted a retrospective cohort study of HCP exposed to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at our academic medical center from March 15, 2020 to May 16, 2020. Exposure during the study period was defined as having contact with patients or other HCP with COVID-19 within 6 feet of distance for at least 90 seconds when HCP’s eyes, nose, or mouth were not covered. HCP with exposures were monitored for symptoms consistent with COVID-19 for 14 days from last exposure and those who developed symptoms were tested for SARS-CoV-2 using RT-PCR. Results We identified 33 exposure events; 19 of which were patient-to-HCP exposures and 14 of which were HCP-to-HCP exposures. These 33 events resulted in 959 exposed HCP among whom 238 (25%) developed one or more symptoms of COVID-19 and required SARS-CoV-2 RT-PCR testing. Testing was performed at 7.1 ± 5.0 (mean ± SD) days from exposure. Of the 238 HCP who were tested, 82% were female and 49% were registered nurses (Table 1). Five HCP tested positive for SARS-CoV-2 by RT-PCR, but one was presumed to have acquired the disease from a household member with confirmed COVID-19. Among the four HCP who were infected due to occupational exposure, three were nurses while one was an environmental service worker (Table 1). Conclusion Despite exposures among HCP, the risk of acquiring symptomatic COVID-19 in the healthcare setting was low with less than 1% of HCP with occupational exposure subsequently diagnosed with COVID-19. With the definition of exposure now changed to at least 15 minutes of close contact without personal protective equipment, we anticipate fewer exposures at our healthcare facility and that much of COVID-19 transmission affecting HCP are due to community exposures. Disclosures All Authors: No reported disclosures

BackgroundCoronavirus disease 2019, caused by severe acute respiratory syndrome coronavirus 2, was declared a global pandemic by the World Health Organization in March 2020.Case presentationWe report a case of a 51-year-old Chinese woman who was evacuated from Wuhan, China and diagnosed with coronavirus disease 2019 infection at a Southern California quarantine facility. Her clinical course was notable for high fevers, night sweats, productive cough, transient leukopenia, lymphopenia, thrombocytopenia, and transaminitis. Evolving hypoxia and infiltrates on chest imaging warranted the trial of an investigational antiviral drug - remdesivir. Our patient recovered and was discharged after 2 weeks of hospitalization.ConclusionsThis case highlights our patient's clinical course, including diagnostic work-up, medical management, and challenges in defining non-infectivity in a relatively unknown disease.

Abstract Background The SARS-CoV-2 pandemic remains a major threat worldwide. Healthcare workers (HCWs) are particularly impacted by the COVID-19 pandemic with high infection rates reported from HCWs in hard-hit regions2,3, raising concerns about nosocomial infections and the effectiveness of personal protective equipment in protecting HCWs. Asymptomatic infection is estimated 17.9% to 33.3%4 and is a common source of transmission5. We designed a HCW testing program to address patient and employee concerns about exposures in the healthcare setting at our 808-bed health system. During the time of employee testing, the mean (range) number of inpatients with a diagnosis of COVID was 30 (22–38) of a mean (range) daily census of 560 (492–602) (approximately 5.4%). Methods This opt-in program offered SARS-CoV-2 testing of asymptomatic HCWs with paired nasopharyngeal or mid-turbinate swab for PCR (Roche) and serum IgG antibody testing (Diazyme). While initially designed as a pilot project in the Emergency Departments and COVID-19 units, it was quickly expanded to a health system-wide initiative. Results From April 22 to June 2, PCR testing was performed on 5826 asymptomatic HCWs with four PCR tests resulting positive (0.09%). Of 5589 serologic tests (anti-SARS-CoV-2 IgG) performed, 57 tested positive (1.02 %). All HCW with a positive IgG had a concurrent negative PCR. Conclusion In this cross-sectional evaluation, the point prevalence of SARS-CoV-2 IgG in asymptomatic HCWs at UC San Diego was less than 1%, supporting modeling estimations at the San Diego County level of very low levels of community exposure at the time of this testing. Further analyses of incidence rates and potential risk factors such as employee roles within the healthcare system, community and healthcare exposures, and home zip code are underway. Asymptomatic HCW testing is a strategy that can provide the perception of additional safety to both the workforce and patients as the health system reopens, while potentially reduce transmission from asymptomatic persons through active case finding and isolation. Disclosures Randy Taplitz, MD, Merck (Advisor or Review Panel member)

Abstract Background As of June 2, 2020, 67,113 cases and 321 deaths due to Coronavirus Disease 19 (COVID-19) have been reported in healthcare personnel (HCP) in the United States. Given the close contact of HCP with individuals with COVID-19, it is important to quantify the risk of acquiring COVID-19 in the healthcare setting. Methods We conducted a retrospective cohort study of HCP exposed to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at our academic medical center from March 15, 2020 to May 16, 2020. Exposure during the study period was defined as having contact with patients or other HCP with COVID-19 within 6 feet of distance for at least 90 seconds when HCP’s eyes, nose, or mouth were not covered. HCP with exposures were monitored for symptoms consistent with COVID-19 for 14 days from last exposure and those who developed symptoms were tested for SARS-CoV-2 using RT-PCR. Results We identified 33 exposure events; 19 of which were patient-to-HCP exposures and 14 of which were HCP-to-HCP exposures. These 33 events resulted in 959 exposed HCP among whom 238 (25%) developed one or more symptoms of COVID-19 and required SARS-CoV-2 RT-PCR testing. Testing was performed at 7.1 ± 5.0 (mean ± SD) days from exposure. Of the 238 HCP who were tested, 82% were female and 49% were registered nurses (Table 1). Five HCP tested positive for SARS-CoV-2 by RT-PCR, but one was presumed to have acquired the disease from a household member with confirmed COVID-19. Among the four HCP who were infected due to occupational exposure, three were nurses while one was an environmental service worker (Table 1). Conclusion Despite exposures among HCP, the risk of acquiring symptomatic COVID-19 in the healthcare setting was low with less than 1% of HCP with occupational exposure subsequently diagnosed with COVID-19. With the definition of exposure now changed to at least 15 minutes of close contact without personal protective equipment, we anticipate fewer exposures at our healthcare facility and that much of COVID-19 transmission affecting HCP are due to community exposures. Disclosures All Authors: No reported disclosures

BackgroundPublic reporting of Clostridioides difficile infection (CDI) using laboratory-identified events has led some institutions to revert from molecular-based tests to less sensitive testing modalities. At one academic medical center, researchers chose to use nucleic acid amplification test alone in CDI diagnosis with institutional protocols aimed at diagnostic stewardship.MethodsA single-center, quasi-experimental study was conducted to introduce and analyze the effects of various diagnostic stewardship interventions. In April 2017 an order report was created to inform providers of patients' recent bowel movements, laxative use, and prior Clostridioides difficile (CD) testing (Intervention 1). In November 2017 nursing staff were empowered to not send nondiarrheal stools for testing (Intervention 2). In February 2019, an interruptive alert was implemented to prevent testing that was not indicated (Intervention 3). CD testing rates and healthcare facility-onset CDI (HO-CDI) rates were compared before and after the interventions using one-way analysis of variance (ANOVA).ResultsAt baseline, testing for CD after 3 days of admission was performed at mean ± standard deviation of 15.9 ± 1.7 tests/1,000 patient-days. After Intervention 1, it decreased to 12.1 ± 1.1 tests. This further decreased to 10.6 ± 0.8 after Intervention 2 and to 8.1 ± 0.1 after Intervention 3 (p < 0.001). HO-CDI cases per 10,000 patient-days declined from 12.7 ± 1.4 cases at baseline to 10.7 ± 1.2 after Intervention 1, to 8.7 ± 2.4 after Intervention 2, and to 5.8 ± 0.2 after Intervention 3 (p = 0.03).ConclusionA multidisciplinary approach optimizing electronic health record support tools and leveraging nursing education can reduce both testing and HO-CDI rates while using the most sensitive testing modality.

During 2016-2018, San Diego County, California, USA, experienced one of the largest hepatitis A outbreaks in the United States in 2 decades. In close partnership with local healthcare systems, San Diego County Public Health led a public health response to the outbreak that focused on a 3-pronged strategy to vaccinate, sanitize, and educate. Healthcare systems administered nearly half of the vaccinations delivered in San Diego County. At University of California San Diego Health, the use of informatics tools assisted with the identification of at-risk populations and with vaccine delivery across outpatient and inpatient settings. In addition, acute care facilities helped prevent further disease transmission by delaying the discharge of patients with hepatitis A who were experiencing homelessness. We assessed the public health roles that acute care hospitals can play during a large community outbreak and the critical nature of ongoing collaboration between hospitals and public health systems in controlling such outbreaks.

ObjectiveTo describe the implementation of technological support important for optimizing clinical management of the COVID-19 pandemic.Materials and methodsOur health system has confirmed prior and current cases of COVID-19. An Incident Command Center was established early in the crisis and helped identify electronic health record (EHR)-based tools to support clinical care.ResultsWe outline the design and implementation of EHR-based rapid screening processes, laboratory testing, clinical decision support, reporting tools, and patient-facing technology related to COVID-19.DiscussionThe EHR is a useful tool to enable rapid deployment of standardized processes. UC San Diego Health built multiple COVID-19-specific tools to support outbreak management, including scripted triaging, electronic check-in, standard ordering and documentation, secure messaging, real-time data analytics, and telemedicine capabilities. Challenges included the need to frequently adjust build to meet rapidly evolving requirements, communication, and adoption, and to coordinate the needs of multiple stakeholders while maintaining high-quality, prepandemic medical care.ConclusionThe EHR is an essential tool in supporting the clinical needs of a health system managing the COVID-19 pandemic.

BackgroundWe compared new Aspergillus Galactomannan Lateral Flow Assay with the newly formatted Aspergillus-specific Lateral Flow device tests for the diagnosis of invasive pulmonary aspergillosis (IPA) in non-neutropenic patients.MethodsWe performed both tests in 82 bronchoalveolar lavage fluid samples from 82 patients at risk for IPA but without underlying haematologic malignancy. Samples were collected between September 2016 and September 2018 at the University of California San Diego, United States. IPA was classified following two published consensus criteria.ResultsClassification of cases varied widely between the two consensus criteria. When using criteria established for the intensive care unit, 26/82 patients (32%) met criteria for proven or putative IPA. Both point-of-care assays showed sensitivities ranging between 58% and 69%, with specificities between 68% and 75%. Sensitivity increased up to 81% when both tests were combined.ConclusionThe study outlines the need for updated, unified and more broadly applicable consensus definitions for classifying IPA in non-neutropenic patients, a work that is currently in progress. Both point-of-care tests showed comparable performance, with sensitivities and specificities in the 60%-70% range when used alone and increasing to 80% when used in combination. The new point-of-care tests may serve a role at the bedside in those with clinical suspicion of IPA.

Volume 61, no. 10, e00954-17, 2017, https://doi.org/10.1128/AAC.00954-17. Materials and Methods, 2nd paragraph, 2nd sentence: “Phages provided by the Biological Defense Research Directorate (BDRD) of the Naval Medical Research Center (AB-Navy1, AB-Navy4, AB-Navy71, AB-Navy97, and AbTP31) were isolated from various environmental samples by using routine isolation techniques, as previously described (9)” should read “Phages provided by the Biological Defense Research Directorate (BDRD) of the Naval Medical Research Center (AB-Navy1, AB-Navy4, AB-Navy97, and AbTP31) were isolated from various environmental samples by using routine isolation techniques, as previously described (9), except for one phage (AB-Navy71, also known as phage vB_Ab-M-G7, DSM strain no. 25639), which was purchased from Liebniz Institute DSMZ (Germany).”

Volume 61, no. 10, e00954-17, 2017, https://doi.org/10.1128/AAC.00954-17. Materials and Methods, 2nd paragraph, 2nd sentence: “Phages provided by the Biological Defense Research Directorate (BDRD) of the Naval Medical Research Center (AB-Navy1, AB-Navy4, AB-Navy71, AB-Navy97, and AbTP31) were isolated from various environmental samples by using routine isolation techniques, as previously described (9)” should read “Phages provided by the Biological Defense Research Directorate (BDRD) of the Naval Medical Research Center (AB-Navy1, AB-Navy4, AB-Navy97, and AbTP31) were isolated from various environmental samples by using routine isolation techniques, as previously described (9), except for one phage (AB-Navy71, also known as phage vB_Ab-M-G7, DSM strain no. 25639), which was purchased from Liebniz Institute DSMZ (Germany).”

Widespread antibiotic use in clinical medicine and the livestock industry has contributed to the global spread of multidrug-resistant (MDR) bacterial pathogens, including Acinetobacter baumannii We report on a method used to produce a personalized bacteriophage-based therapeutic treatment for a 68-year-old diabetic patient with necrotizing pancreatitis complicated by an MDR A. baumannii infection. Despite multiple antibiotic courses and efforts at percutaneous drainage of a pancreatic pseudocyst, the patient deteriorated over a 4-month period. In the absence of effective antibiotics, two laboratories identified nine different bacteriophages with lytic activity for an A. baumannii isolate from the patient. Administration of these bacteriophages intravenously and percutaneously into the abscess cavities was associated with reversal of the patient's downward clinical trajectory, clearance of the A. baumannii infection, and a return to health. The outcome of this case suggests that the methods described here for the production of bacteriophage therapeutics could be applied to similar cases and that more concerted efforts to investigate the use of therapeutic bacteriophages for MDR bacterial infections are warranted.

Widespread antibiotic use in clinical medicine and the livestock industry has contributed to the global spread of multidrug-resistant (MDR) bacterial pathogens, including Acinetobacter baumannii We report on a method used to produce a personalized bacteriophage-based therapeutic treatment for a 68-year-old diabetic patient with necrotizing pancreatitis complicated by an MDR A. baumannii infection. Despite multiple antibiotic courses and efforts at percutaneous drainage of a pancreatic pseudocyst, the patient deteriorated over a 4-month period. In the absence of effective antibiotics, two laboratories identified nine different bacteriophages with lytic activity for an A. baumannii isolate from the patient. Administration of these bacteriophages intravenously and percutaneously into the abscess cavities was associated with reversal of the patient's downward clinical trajectory, clearance of the A. baumannii infection, and a return to health. The outcome of this case suggests that the methods described here for the production of bacteriophage therapeutics could be applied to similar cases and that more concerted efforts to investigate the use of therapeutic bacteriophages for MDR bacterial infections are warranted.

In the context of large-scale human system immunology studies, controlling for technical and biological variability is crucial to ensure that experimental data support research conclusions. In this study, we report on a universal workflow to evaluate both technical and biological variation in multiparameter flow cytometry, applied to the development of a 10-color panel to identify all major cell populations and T cell subsets in cryopreserved PBMC. Replicate runs from a control donation and comparison of different gating strategies assessed the technical variability associated with each cell population and permitted the calculation of a quality control score. Applying our panel to a large collection of PBMC samples, we found that most cell populations showed low intraindividual variability over time. In contrast, certain subpopulations such as CD56 T cells and Temra CD4 T cells were associated with high interindividual variability. Age but not gender had a significant effect on the frequency of several populations, with a drastic decrease in naive T cells observed in older donors. Ethnicity also influenced a significant proportion of immune cell population frequencies, emphasizing the need to account for these covariates in immune profiling studies. We also exemplify the usefulness of our workflow by identifying a novel cell-subset signature of latent tuberculosis infection. Thus, our study provides a universal workflow to establish and evaluate any flow cytometry panel in systems immunology studies.

We describe the sampling of sixty-three uncultured hospital air samples collected over a six-month period and analysis using shotgun metagenomic sequencing. Our primary goals were to determine the longitudinal metagenomic variability of this environment, identify and characterize genomes of potential pathogens and determine whether they are atypical to the hospital airborne metagenome. Air samples were collected from eight locations which included patient wards, the main lobby and outside. The resulting DNA libraries produced 972 million sequences representing 51 gigabases. Hierarchical clustering of samples by the most abundant 50 microbial orders generated three major nodes which primarily clustered by type of location. Because the indoor locations were longitudinally consistent, episodic relative increases in microbial genomic signatures related to the opportunistic pathogens Aspergillus, Penicillium and Stenotrophomonas were identified as outliers at specific locations. Further analysis of microbial reads specific for Stenotrophomonas maltophilia indicated homology to a sequenced multi-drug resistant clinical strain and we observed broad sequence coverage of resistance genes. We demonstrate that a shotgun metagenomic sequencing approach can be used to characterize the resistance determinants of pathogen genomes that are uncharacteristic for an otherwise consistent hospital air microbial metagenomic profile.

[This corrects the article DOI: 10.1371/journal.pone.0160124.].