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Among 133 cancer outpatients diagnosed with influenza between 2016 and 2018, 110 (83%) were prescribed oseltamivir. Among 109 with a known symptom onset date, 53% presented for care and 31% were prescribed oseltamivir within 48 hours. Patient/provider education and rapid diagnostics are needed to improve early oseltamivir use among cancer patients with influenza.

Background There is renewed interest in CMV-specific humoral immune protection due to recent murine data suggesting that strain-specific antibodies may inhibit CMV cell-to-cell spread (Science. 2019; 363:288). To characterize the nature of antibody protection against CMV after HCT, we tested pre-HCT sera in a cohort of CMV D-R+ allogeneic HCT recipients from the pre-letermovir era using VirScan, a technology that measures pathogen-specific humoral immunity (IgG) at the epitope level. Methods Patients (age 0-70 years) who received 1st, myeloablative, HCT for acute leukemia or myelodysplastic syndrome and who underwent PCR surveillance and preemptive therapy were included. VirScan was used on sera collected pre-HCT. Cumulative incidence curves and multivariable Cox regression analyses were used to determine the association of pre-HCT CMV antibody epitopes scores with CMV reactivation (any, >150 IU/mL, >500 IU/mL) in the first 8 weeks post-HCT. Results 170 CMV D-R+ HCT recipients were tested a median of 26 days (range 7-37 days) prior to HCT and had a median of 37 CMV antibody epitopes (IQR 29-50 epitopes, range 14-77 epitopes). The cumulative incidence of CMV reactivation was higher in patients with greater pre-HCT CMV antibody epitopes at each evaluated PCR threshold (Figure 1) and the effect appeared more pronounced in adults (Figure 2). High (≥ 4th quartile vs. 1st quartile), pre-HCT CMV antibody epitopes were associated with an increased risk of any CMV reactivation (adjusted Hazard Ratio [aHR]=4.1, 95% confidence interval [CI] 2.1-7.7, p< 0.001) and at >150 IU/mL (aHR=3.0, 95% CI 1.4-6.5 p=0.006) after adjusting for age, HLA-matching, and pre-HCT T-cell depletion ( >150 IU/mL only). Figure 1Figure 2 Conclusion We observed a paradoxically increased risk of CMV reactivation in patients with high pre-HCT CMV VirScan scores. It is possible that pre-HCT CMV-specific humoral immunity as measured by VirScan is reflective of the burden of latent CMV or that CMV-specific antibodies may mediate antibody-dependent enhancement after HCT and thus facilitate reactivation. Future studies are needed to validate our findings in diverse cohorts and to elucidate the underlying mechanism of increased VirScan scores and associated risks of CMV reactivation. Disclosures Rachel A. Bender Ignacio, MD, MPH, Abbvie: Advisor/Consultant|SeaGen: Advisor/Consultant Joshua A. Hill, MD, Allovir: Advisor/Consultant|Allovir: Grant/Research Support|Covance/CSL: Advisor/Consultant|CRISPR: Advisor/Consultant|Deverra: Grant/Research Support|Gilead: Grant/Research Support|Karius: Advisor/Consultant|Karius: Grant/Research Support|Merck: Grant/Research Support|Octapharma: Advisor/Consultant|OptumHealth: Advisor/Consultant|Oxford Immunotec: Grant/Research Support|Pfizer: Advisor/Consultant|Symbio: Advisor/Consultant|Takeda: Advisor/Consultant Geoffrey Hill, M.D., FRACP, FRCPA, Applied Molecular Transport: Grant/Research Support|Compass Therapeutics: Grant/Research Support|Generon Corporation: Advisor/Consultant|Heat Biologics: Grant/Research Support|iTeos Therapeutics: Advisor/Consultant|iTeos Therapeutics: Grant/Research Support|Laevoroc Oncology: Grant/Research Support|NapaJen Pharma: Advisor/Consultant|Neoleukin Therapeutics: Advisor/Consultant|Serplus Technology: Grant/Research Support|Syndax Pharmaceuticals: Grant/Research Support Michael J. Boeckh, MD PhD, Allovir: Advisor/Consultant|Amazon: Grant/Research Support|Ansun Biopharma: Grant/Research Support|EvrysBio: Advisor/Consultant|Gates Ventures: Grant/Research Support|Gilead Sciences: Advisor/Consultant|Gilead Sciences: Grant/Research Support|GlaxoSmithKline: Advisor/Consultant|GlaxoSmithKline: Grant/Research Support|Helocyte: Advisor/Consultant|Janssen: Advisor/Consultant|Janssen: Grant/Research Support|Kyorin Pharmaceuticals: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support|Moderna: Advisor/Consultant|Moderna: Grant/Research Support|Regeneron: Grant/Research Support|ReViral: Advisor/Consultant|Symbio: Advisor/Consultant|Takeda: Grant/Research Support|Vir Biotechnology: Advisor/Consultant|Vir Biotechnology: Grant/Research Support.

We examined associations between specific antibiotic exposures and progression to lower respiratory tract disease (LRTD) following individual respiratory viral infections (RVIs) after hematopoietic cell transplantation (HCT). We analyzed allogeneic HCT recipients of all ages with their first RVI during the first 100 days post-HCT. For the 21 days before RVI onset, we recorded any receipt of specific groups of antibiotics, and the cumulative sum of the number of antibiotics received for each day (antibiotic-days). We used Cox proportional hazards models to assess the relationship between antibiotic exposure and progression to LRTD. Among 469 patients with RVI, 124 progressed to LRTD. Compared to no antibiotics, use of antibiotics with broad anaerobic activity in the prior 21 days was associated with progression to LRTD after adjusting for age, virus type, hypoalbuminemia, neutropenia, steroid use, and monocytopenia (HR 2.2, 95% CI 1.1-4.1). Greater use of those antibiotics (≥7 antibiotic days) was also associated with LRTD in adjusted models (HR 2.2, 95% CI 1.1-4.3). Results were similar after adjusting for lymphopenia instead of monocytopenia. Antibiotic use is associated with LRTD after RVI across different viruses in HCT recipients. Prospective studies using anaerobe-sparing antibiotics should be explored to assess impact on LRTD in patients undergoing HCT.

Background Following a meropenem shortage, we implemented a postprescription review with feedback (PPRF) in November 2015 with mandatory infectious disease (ID) consultation for all meropenem and imipenem courses > 72 hours. Providers were made aware of the policy via an electronic alert at the time of ordering. Methods A retrospective study was conducted at the University of Washington Medical Center (UWMC) and Harborview Medical Center (HMC) to evaluate the impact of the policy on antimicrobial consumption and clinical outcomes pre- and postintervention during a 6-year period. Antimicrobial use was tracked using days of therapy (DOT) per 1000 patient-days, and data were analyzed by an interrupted time series. Results There were 4066 and 2552 patients in the pre- and postintervention periods, respectively. Meropenem and imipenem use remained steady until the intervention, when a marked reduction in DOT/1000 patient-days occurred at both hospitals (UWMC: percentage change −72.1% (95% confidence interval [CI] −76.6, −66.9), P < .001; HMC: percentage change −43.6% (95% CI −59.9, −20.7), P = .001). Notably, although the intervention did not address antibiotic use until 72 hours after initiation, there was a significant decline in meropenem and imipenem initiation (“first starts”) in the postintervention period, with a 64.9% reduction (95% CI 58.7, 70.2; P < .001) at UWMC and 44.7% reduction (95% CI 28.1, 57.4; P < .001) at HMC. Conclusions PPRF and mandatory ID consultation for meropenem and imipenem use beyond 72 hours resulted in a significant and sustained reduction in the use of these antibiotics and notably impacted their up-front usage.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic demonstrates the need for accurate and convenient approaches to diagnose and therapeutically monitor respiratory viral infections. We demonstrated that self-sampling with mid-nasal foam swabs is well-tolerated and provides quantitative viral output concordant with flocked swabs. Using longitudinal home-based self-sampling, we demonstrate that nasal cytokine levels correlate and cluster according to immune cell of origin. Periods of stable viral loads are followed by rapid elimination, which could be coupled with cytokine expansion and contraction. Nasal foam swab self-sampling at home provides a precise, mechanistic readout of respiratory virus shedding and local immune responses.

Background Contemporary information regarding fever and neutropenia (FN) management, including approaches to antibacterial prophylaxis, empiric therapy, and de-escalation across US cancer centers, is lacking. Methods This was a self-administered, electronic, cross-sectional survey of antimicrobial stewardship physicians and pharmacists at US cancer centers. The survey ascertained institutional practices and individual attitudes on FN management in high-risk cancer patients. A 5-point Likert scale assessed individual attitudes. Results Providers from 31 of 86 hospitals (36%) responded, and FN management guidelines existed in most (29/31, 94%) hospitals. Antibacterial prophylaxis was recommended in 27/31 (87%) hospitals, with levofloxacin as the preferred agent (23/27, 85%). Cefepime was the most recommended agent for empiric FN treatment (26/29, 90%). Most institutional guidelines (26/29, 90%) recommended against routine addition of empiric gram-positive agents except for specific scenarios. Eighteen of 29 (62%) hospitals explicitly provided guidance on de-escalation of empiric, systemic antibacterial therapy; however, timing of de-escalation was variable according to clinical scenario. Among 34 individual respondents, a majority agreed with use of antibiotic prophylaxis in high-risk patients (25, 74%). Interestingly, only 10 (29%) respondents indicated agreement with the statement that benefits of antibiotic prophylaxis outweigh potential harms. Conclusion Most US cancer centers surveyed had institutional FN management guidelines. Antibiotic de-escalation guidance was lacking in nearly 40% of centers, with heterogeneity in approaches when recommendations existed. Further research is needed to inform FN guidelines on antibacterial prophylaxis and therapy de-escalation.

BACKGROUND: Chimeric antigen receptor (CAR) T cells targeting B-cell maturation antigen (BCMA-CARTx) are an emerging treatment for relapsed or refractory multiple myeloma (R/R MM). OBJECTIVES: Characterize the epidemiology of infections, risk factors for infection, and pathogen-specific humoral immunity in patients receiving BCMA-CARTx for R/R MM. STUDY DESIGN: We performed a retrospective cohort study in 32 adults with R/R MM enrolled in two single-institution phase 1 clinical trials of BCMA-CARTx administered after lymphodepleting chemotherapy alone (n=22) or with (n=10) a gamma secretase inhibitor (GSI). We tested serum prior to and up to approximately 180 days after BCMA-CARTx for measles-specific IgG and for any viral-specific IgG using a systematic viral epitope scanning assay to describe the kinetics of total and pathogen-specific IgG levels pre- and post-BCMA-CARTx. We identified microbiologically documented infections to determine infection incidence and used Poisson regression to explore risk factors for infections within 180 days after BCMA-CARTx. RESULTS: Most individuals developed severe neutropenia, lymphopenia and hypogammaglobulinemia after BCMA-CARTx. Grade ≥3 cytokine release syndrome (CRS; Lee criteria) occurred in 16% of participants; corticosteroids and/or tocilizumab were administered to 50% of participants. Before BCMA-CARTx, 28/32 (88%) participants had an IgG

SARS-CoV-2 vaccine clinical trials assess efficacy against disease (VEDIS), the ability to block symptomatic COVID-19. They only partially discriminate whether VEDIS is mediated by preventing infection completely, which is defined as detection of virus in the airways (VESUSC), or by preventing symptoms despite infection (VESYMP). Vaccine efficacy against transmissibility given infection (VEINF), the decrease in secondary transmissions from infected vaccine recipients, is also not measured. Using mathematical modeling of data from King County Washington, we demonstrate that if the Moderna (mRNA-1273QS) and Pfizer-BioNTech (BNT162b2) vaccines, which demonstrated VEDIS &gt, 90% in clinical trials, mediate VEDIS by VESUSC, then a limited fourth epidemic wave of infections with the highly infectious B.1.1.7 variant would have been predicted in spring 2021 assuming rapid vaccine roll out. If high VEDIS is explained by VESYMP, then high VEINF would have also been necessary to limit the extent of this fourth wave. Vaccines which completely protect against infection or secondary transmission also substantially lower the number of people who must be vaccinated before the herd immunity threshold is reached. The limited extent of the fourth wave suggests that the vaccines have either high VESUSC or both high VESYMP and high VEINF against B.1.1.7. Finally, using a separate intra-host mathematical model of viral kinetics, we demonstrate that a 0.6 log vaccine-mediated reduction in average peak viral load might be sufficient to achieve 50% VEINF, which suggests that human challenge studies with a relatively low number of infected participants could be employed to estimate all three vaccine efficacy metrics.

Voriconazole (VCZ) was one of the first mold-active triazoles available; however, its current use among high-risk hematology populations is unknown as the uptake of posaconazole (PCZ) and isavuconazole (ISZ) increases. We evaluated the usage and therapeutic level attainment of VCZ in hematopoietic cell transplantation (HCT) and chimeric antigen receptor T cell (CAR-T) therapy patients at our cancer center. Electronic medical records for all adult HCT or CAR-T patients with an order for VCZ, PCZ, or ISV between January 1, 2018, and June 30, 2020, were extracted. Clinical characteristics, VCZ indication, trough VCZ levels, and frequency of VCZ initiation from 6 months before to 6 months after HCT/CAR-T infusion in consecutive HCT/CAR-T recipients within the study period (infusion between July 1, 2018, and January 1, 2020) were assessed. The association between relevant clinical characteristics and the attainment of subtherapeutic or supratherapeutic levels was also evaluated. Of 468 patients prescribed mold-active triazoles, 256 (54.7%) were prescribed VCZ, 324 (69.2%) PCZ, and 60 (12.8%) ISZ; 152/468 (32.5%) treatment regimens were sequentially modified to alternate mold-active triazoles. Among consecutive HCT and CAR-T recipients at our center, evaluated 6 months pre- or post- HCT/ CAR-T, VCZ was commonly initiated before or after allogeneic HCT (102/381, 26.8%), with most use in the first 30 days after stem cell infusion (40/381, 10.5%); VCZ use was less common in autologous HCT (13/276, 4.7%) and CAR-T (10/153, 6.5%). Of 223 VCZ orders that met inclusion for analysis, indications included empiric treatment in 108/223 (48.4%), directed therapy in 25/223 (11.2%), primary prophylaxis in 69/223 (30.9%) and secondary prophylaxis in 21/223 (9.4%). Of 223 eligible VCZ patients, 144 (64.6%) had at least 1 VCZ level measured during the study period; 75/144 (52.1%) had a therapeutic VCZ level (1.0-5.5 mg/L) at the first measurement (median 2.8mg/L [range 0.1-13.5]) at a median of 6 days of therapy, with 26.4% subtherapeutic and 21.5% supratherapeutic; 46/88 (52.3%) were therapeutic at the second measurement (2.1mg/L [0.1-9.9]) at a median of 17 days of therapy; and 33/48 (68.8%) at the third (2.3mg/L [0.1-7.7]) at a median of 29 days. In multivariable analysis of factors associated with sub- or supratherapeutic levels (body mass index ≥30, concurrent omeprazole use, concurrent letermovir use, indication for VCZ, history/timeframe of HCT), the only significant association was lower odds of a supratherapeutic VCZ level among those undergoing HCT within the previous 30 days compared to those without a history of HCT. VCZ continues to remain an important option in the treatment and prevention of invasive fungal infections in an era when alternative oral mold-active triazoles are available. In spite of long-standing experience with VCZ prescribing, therapeutic level attainment remains a challenge.

This cross-sectional study examines serological test results for protective antibodies for measles and mumps among patients with hematologic malignant neoplasm or solid tumors., Key Points Question What is the seroprevalence of measles and mumps among patients with cancer? Findings In this cross-sectional seroprevalence study that involved 959 patients with cancer, 25% of patients lacked protective antibodies for measles and 38% lacked antibodies for mumps. Younger patients (aged 30-59 years), those with hematologic malignant neoplasms, and recipients of a hematopoietic stem cell transplant had a significantly lower seroprevalence for both measles and mumps. Meaning Low seroprevalence of measles and mumps among patients with cancer places them at increased risk for infection during measles or mumps outbreaks in the community., Importance Although patients with cancer are at an increased risk of infection-related complications, few studies have characterized their vulnerability to measles and mumps. Given the recent outbreaks and increased community vaccine hesitancy, understanding measles and mumps immunity within this population is vital. Objectives To identify a point prevalence estimate of protective measles and mumps antibodies among ambulatory patients with cancer. Design, Setting, and Participants In this cross-sectional study, residual clinical plasma samples were obtained from consecutive patients with cancer at Seattle Cancer Care Alliance/Fred Hutchinson Cancer Research Center in Seattle, Washington, in August 2019. These samples were tested for measles and mumps IgG using a commercial enzyme-linked immunosorbent assay. Patients without cancer were excluded from the analysis. Exposures Patient age, sex, self-reported race and ethnicity, primary disease, receipt of chemotherapy in the past 30 days before sample collection, hematopoietic cell transplant (HCT) history, and date of most recent intravenous immunoglobulin treatment were abstracted from electronic medical records. Main Outcomes and Measures Measles and mumps IgG seroprevalence, defined as the proportion of patients with positive antibody test results, was measured overall and among the subgroups. Results Of the 959 patients included in the analysis, 510 (53%) were male individuals and the mean (SD) age at sample collection was 60 (15) years. Most patients (576 [60%]) had a malignant solid tumor, and 383 patients (40%) had a hematologic malignant neoplasm; 146 patients (15%) had an HCT history. Overall, the seroprevalence of measles antibodies was 0.75 (95% CI, 0.72-0.78), and the seroprevalence of mumps antibodies was 0.62 (95% CI, 0.59-0.65). The lowest seroprevalences were among patients with a hematologic malignant neoplasm (0.63 for measles and 0.48 for mumps), those with a history of HCT (0.46 for measles and 0.29 for mumps), and those aged 30 to 59 years (0.49-0.63 for measles and 0.41-0.58 for mumps). Conclusions and Relevance In this study, 25% of ambulatory patients with cancer lacked protective antibodies for measles and 38% lacked protective antibodies for mumps. Deficits in protective antibodies underscore patients’ increased risk during outbreaks and emphasize the need for community-based efforts to increase herd immunity to protect this population.

BACKGROUND Little is known about pathogen-specific humoral immunity after chimeric antigen receptor–modified T (CAR-T) cell therapy for B cell malignancies. METHODS We conducted a prospective cross-sectional study of CD19-targeted or B cell maturation antigen–targeted (BCMA-targeted) CAR-T cell therapy recipients at least 6 months posttreatment and in remission. We measured pathogen-specific IgG against 12 vaccine-preventable infections and the number of viral and bacterial epitopes to which IgG was detected (“epitope hits”) using a serological profiling assay. The primary outcome was the proportion of participants with IgG levels above a threshold correlated with seroprotection for vaccine-preventable infections. RESULTS We enrolled 65 children and adults a median of 20 months after CD19- (n = 54) or BCMA- (n = 11) CAR-T cell therapy. Among 30 adults without IgG replacement therapy (IGRT) in the prior 16 weeks, 27 (90%) had hypogammaglobulinemia. These individuals had seroprotection to a median of 67% (IQR, 59%–73%) of tested infections. Proportions of participants with seroprotection per pathogen were comparable to population-based studies, but most individuals lacked seroprotection to specific pathogens. Compared with CD19-CAR-T cell recipients, BCMA-CAR-T cell recipients were half as likely to have seroprotection (prevalence ratio, 0.47; 95% CI, 0.18–1.25) and had fewer pathogen-specific epitope hits (mean difference, –90 epitope hits; 95% CI, –157 to –22). CONCLUSION Seroprotection for vaccine-preventable infections in adult CD19-CAR-T cell recipients was comparable to the general population. BCMA-CAR-T cell recipients had fewer pathogen-specific antibodies. Deficits in both groups support the need for vaccine and immunoglobulin replacement therapy studies. FUNDING Swiss National Science Foundation (Early Postdoc Mobility grant P2BSP3_188162), NIH/National Cancer Institute (NIH/NCI) (U01CA247548 and P01CA018029), NIH/NCI Cancer Center Support Grants (P30CA0087-48 and P30CA015704-44), American Society for Transplantation and Cellular Therapy, and Juno Therapeutics/BMS., In this prospective study, we investigated antibodies against vaccine-preventable infections and other pathogen-specific antibodies in individuals with remission after CAR-T cell therapy for B lineage malignancies.

Recipients of chimeric antigen receptor-modified T (CAR-T) cell therapies for B-cell malignancies are immunocompromised and at risk for serious infections. Vaccine immunogenicity is unknown in this population. We conducted a prospective observational study of the humoral immunogenicity of 2019-2020 inactivated influenza vaccines (IIV) in children and adults immediately prior to (n=7) or 13-57 months after (n=15) CD19-, CD20-, or BCMA-targeted CAR-T-cell therapy, as well as controls (n=8). Individuals post-CAR-T-cell therapy were in remission. We tested for antibodies to 4 vaccine strains at baseline and ≥1 time point after IIV using neutralization and hemagglutination inhibition assays. An antibody response was defined as a ≥4-fold titer increase from baseline at the first post-vaccine time point. Baseline A(H1N1) titers in the CAR-T cohorts were significantly lower compared to controls. Antibody responses to ≥1 vaccine strain occurred in 2 (29%) individuals before CAR-T-cell therapy; one individual maintained a response for >3 months post-CAR-T-cell therapy. Antibody responses to ≥1 vaccine strain occurred in 6 (40%) individuals vaccinated after CAR-T-cell therapy. An additional 2 (29%) and 6 (40%) individuals had ≥2-fold increases (at any time) in the pre- and post-CAR-T cohorts, respectively. There were no identified clinical or immunologic predictors of antibody responses. Neither severe hypogammaglobulinemia nor B-cell aplasia precluded antibody responses. These data support consideration for vaccination before and after CAR-T-cell therapy for influenza and other relevant pathogens such as SARS-CoV-2, irrespective of hypogammaglobulinemia or B-cell aplasia. Larger studies are needed to determine correlates of vaccine immunogenicity and durability in CAR-T-cell therapy recipients.Key PointsInfluenza vaccination was immunogenic pre- and post-CAR-T-cell therapy, despite hypogammaglobulinemia and B-cell aplasia.Vaccination with inactivated vaccines can be considered before CAR-T-cell therapy and in individuals with remission after therapy.

This cross-sectional study examines whether racial and/or ethnic minority, female, and older adults are underrepresented in vaccine clinical trials compared with the US population., Key Points Question Do vaccine clinical trials equitably represent individuals who identify as members of underrepresented racial/ethnic groups, are women, and are people aged 65 years or older? Findings In this cross-sectional study of 230 US-based clinical trials with 219 555 participants, Black or African American, American Indian or Alaska Native, Hispanic or Latino, and older adults were underrepresented and women were overrepresented compared with the US population. Meaning The findings suggest that diversity enrollment targets are needed for vaccine trials in the US., Importance Medical research has not equitably included members of racial/ethnic minority groups or female and older individuals. There are limited data on participant demographic characteristics in vaccine trials despite the importance of these data to current trials aimed at preventing coronavirus disease 2019. Objective To investigate whether racial/ethnic minority groups and female and older adults are underrepresented among participants in vaccine clinical trials. Design, Setting, and Participants This cross-sectional study examined data from completed US-based vaccine trials registered on ClinicalTrials.gov from July 1, 2011, through June 30, 2020. The terms vaccine, vaccination, immunization, and inoculation were used to identify trials. Only those addressing vaccine immunogenicity or efficacy of preventative vaccines were included. Main Outcomes and Measures The numbers and percentages of racial/ethnic minority, female, and older individuals compared with US census data from 2011 and 2018. Secondary outcome measures were inclusion by trial phase and year of completion. Results A total of 230 US-based trials with 219 555 participants were included in the study. Most trials were randomized (180 [78.3%]), included viral vaccinations (159 [69.1%]), and represented all trial phases. Every trial reported age and sex; 134 (58.3%) reported race and 79 (34.3%) reported ethnicity. Overall, among adult study participants, White individuals were overrepresented (77.9%; 95% CI, 77.4%-78.4%), and Black or African American individuals (10.6%; 95% CI, 10.2%-11.0%) and American Indian or Alaska Native individuals (0.4%; 95% CI, 0.3%-0.5%) were underrepresented compared with US census data; enrollment of Asian individuals was similar (5.7%; 95% CI, 5.5%-6.0%). Enrollment of Hispanic or Latino individuals (11.6%; 95% CI, 11.1%-12.0%) was also low even among the limited number of adult trials reporting ethnicity. Adult trials were composed of more female participants (75 325 [56.0%]), but among those reporting age as a percentage, enrollment of participants who were aged 65 years or older was low (12.1%; 95% CI, 12.0%-12.3%). Black or African American participants (10.1%; 95% CI, 9.7%-10.6%) and Hispanic or Latino participants (22.5%; 95% CI, 21.6%-23.4%) were also underrepresented in pediatric trials. Among trials reporting race/ethnicity, 65 (48.5%) did not include American Indian or Alaska Native participants and 81 (60.4%) did not include Hawaiian or Pacific Islander participants. Conclusions and Relevance This cross-sectional study found that among US-based vaccine clinical trials, members of racial/ethnic minority groups and older adults were underrepresented, whereas female adults were overrepresented. These findings suggest that diversity enrollment targets should be included for all vaccine trials targeting epidemiologically important infections.

Background High morbidity and mortality have been observed in patients with cancer and coronavirus disease 2019 (COVID-19); however, there are limited data on antimicrobial use, coinfections, and viral shedding. Methods We conducted a retrospective cohort study of adult patients at the Seattle Cancer Care Alliance diagnosed with COVID-19 between February 28, 2020 and June 15, 2020 to characterize antimicrobial use, coinfections, viral shedding, and outcomes within 30 days after diagnosis. Cycle threshold values were used as a proxy for viral load. We determined viral clearance, defined as 2 consecutive negative results using severe acute respiratory syndrome coronavirus 2 reverse-transcription polymerase chain reaction results through July 30, 2020. Results Seventy-one patients were included with a median age of 61 years; 59% had a solid tumor. Only 3 patients had documented respiratory bacterial coinfection. Empiric antibiotics for pneumonia were prescribed more frequently early in the study period (February 29–March 28, 2020; 12/34) compared to the later period (March 29–June 15, 2020; 2/36) (P = .002). The median number of days from symptom onset to viral clearance was 37 days with viral load rapidly declining in the first 7–10 days after symptom onset. Within 30 days of diagnosis, 29 (41%) patients were hospitalized and 12 (17%) died. Each additional comorbidity was associated with 45% lower odds of days alive and out of hospital in the month following diagnosis in adjusted models. Conclusions Patients at a cancer center, particularly those with multiple comorbidities, are at increased risk of poor outcomes from COVID-19. Prolonged viral shedding is frequently observed among cancer patients, and its implications on transmission and treatment strategies warrant further study.

Ongoing SARS-CoV-2 vaccine trials assess vaccine efficacy against disease (VEDIS), the ability of a vaccine to block symptomatic COVID-19. They will only partially discriminate whether VEDIS is mediated by preventing infection as defined by the detection of virus in the airways (vaccine efficacy against infection defined as VESUSC), or by preventing symptoms despite breakthrough infection (vaccine efficacy against symptoms or VESYMP). Vaccine efficacy against infectiousness (VEINF), defined as the decrease in secondary transmissions from infected vaccine recipients versus from infected placebo recipients, is also not being measured. Using mathematical modeling of data from King County Washington, we demonstrate that if the Moderna and Pfizer vaccines, which have observed VEDIS>90%, mediate VEDIS predominately by complete protection against infection, then prevention of a fourth epidemic wave in the spring of 2021, and associated reduction of subsequent cases and deaths by 60%, is likely to occur assuming rapid enough vaccine roll out. If high VEDIS is explained primarily by reduction in symptoms, then VEINF>50% will be necessary to prevent or limit the extent of this fourth epidemic wave. The potential added benefits of high VEINF would be evident regardless of vaccine allocation strategy and would be enhanced if vaccine roll out rate is low or if available vaccines demonstrate waning immunity. Finally, we demonstrate that a 1.0 log vaccine-mediated reduction in average peak viral load might be sufficient to achieve VEINF=60% and that human challenge studies with 104 infected participants, or clinical trials in a university student population could estimate VESUSC, VESYMP and VEINF using viral load metrics.

Background Inappropriate testing for Clostridioides difficile leads to overdiagnosis of C difficile infection (CDI). We determined the effect of a computerized clinical decision support (CCDS) order set on C difficile polymerase chain reaction (PCR) test utilization and clinical outcomes. Methods This study is an interrupted time series analysis comparing C difficile PCR test utilization, hospital-onset CDI (HO-CDI) rates, and clinical outcomes before and after implementation of a CCDS order set at 2 academic medical centers: University of Washington Medical Center (UWMC) and Harborview Medical Center (HMC). Results Compared with the 20-month preintervention period, during the 12-month postimplementation of the CCDS order set, there was an immediate and sustained reduction in C difficile PCR test utilization rates at both hospitals (HMC, −28.2% [95% confidence interval {CI}, −43.0% to −9.4%], P = .005; UWMC, −27.4%, [95% CI, −37.5% to −15.6%], P Conclusions Computerized clinical decision support tools can improve C difficile diagnostic test stewardship without causing harm. Additional studies are needed to identify key elements of CCDS tools to further optimize C difficile testing and assess their effect on adverse clinical outcomes.

Background Epstein-Barr virus (EBV) infection is a major cause of malignancy worldwide. Maternal antibody is thought to prevent EBV infection because it is uncommon in early infancy. Maternal HIV infection is associated with an increased incidence of EBV infection in exposed infants, which we hypothesized results from impaired transfer of EBV-neutralizing maternal antibodies. Methods Among Ugandan infants followed for EBV acquisition from birth, we measured antibody binding to EBV glycoproteins (gp350, gH/gL) involved in B-cell and epithelial-cell entry, as well as viral neutralization and antibody-dependent cellular cytotoxicity (ADCC) activity in plasma samples prior to infection. These serologic data were analyzed for differences between HIV-exposed uninfected (HEU) and HIV-unexposed (HUU) infants, and for associations with incident infant EBV infection. Results HEU infants had significantly higher titers than HUU infants for all EBV-binding and neutralizing antibodies measured (P < .01) but not ADCC activity, which was similar between groups. No antibody measure was associated with a decreased risk of EBV acquisition in the cohort. Conclusions Our findings indicate that in this cohort maternal antibody did not protect infants against EBV infection through viral neutralization. The identification of protective nonneutralizing antibody functions would be invaluable for the development of an EBV vaccine.

Background Inappropriate testing for Clostridioides difficile leads to overdiagnosis of C difficile infection (CDI). We determined the effect of a computerized clinical decision support (CCDS) order set on C difficile polymerase chain reaction (PCR) test utilization and clinical outcomes. Methods This study is an interrupted time series analysis comparing C difficile PCR test utilization, hospital-onset CDI (HO-CDI) rates, and clinical outcomes before and after implementation of a CCDS order set at 2 academic medical centers: University of Washington Medical Center (UWMC) and Harborview Medical Center (HMC). Results Compared with the 20-month preintervention period, during the 12-month postimplementation of the CCDS order set, there was an immediate and sustained reduction in C difficile PCR test utilization rates at both hospitals (HMC, −28.2% [95% confidence interval {CI}, −43.0% to −9.4%], P = .005; UWMC, −27.4%, [95% CI, −37.5% to −15.6%], P, Implementation of a computerized clinical decision support (CCDS) order set significantly reduced C difficile PCR test utilization rates and was not associated with an increase in severe CDI or CDI-related complications including ICU transfer, 30-day mortality, and toxic megacolon.

Blood transfusion is fundamental in managing hematologic malignancies. We sought to evaluate the need and availability of blood products for patients with hematological malignancies at Uganda Cancer Institute. We prospectively studied the demand and supply of blood for patients with thrombocytopenia (platelet count ≤50 × 109/L), anemia (hemoglobin ≤10 g/dL), and bleeding (WHO grade ≥2). We used Poisson generalized estimating equation regression models for longitudinal binary outcomes. Among 91 patients, the median age was 26 years (IQR, 11–47). Thrombocytopenia occurred on ≥1 day in 58% of patients and on 49% of hospital days. Platelets were transfused to 39% of patients. The mean number of platelet units requested per day was 16.2 (range 0–30); 5.1 (range 0–15) were received. Anemia occurred on ≥1 day in 90% of patients; on 78% of days; and 68% received at least one blood transfusion. The mean number of blood units requested was 36.3 (range 8–57) units per day; 14 (range 0–30) were received. Bleeding occurred on ≥1 day in 19% of patients on 8% of hospital days. Thrombocytopenia and anemia were common, but product availability was substantially below that requested. We recommend increased blood collection and adherence to strict transfusion triggers as strategies to improve blood availability.

Background Cancer patients are at high risk for serious complications due to influenza. Early treatment with neuraminidase inhibitors (NAIs) is recommended for high-risk patients with suspected or documented influenza. Limited data exist on timing of presentation to care and ambulatory management of cancer patients with influenza. We sought to characterize antimicrobial prescribing and outcomes among patients with influenza at a large cancer center. Methods We selected consecutive patients seen in the ambulatory cancer clinic with laboratory confirmed influenza between January 1, 2016 and December 31, 2018 for chart review. A lab-developed multiplex PCR assay was used with a turnaround time of about 24 hours. We obtained demographics, symptoms at first clinic encounter (day 0), viral testing, NAI and antibiotic prescribing, and clinical outcomes. Results Of 138 charts reviewed, 133 (96%) were eligible for analysis. 109 (82%) had an underlying hematologic malignancy. 84 (63%) tested positive for influenza A and 49 for influenza B. 58 (44%) presented to care within 48 hours of symptom onset (F1). The most commonly reported symptoms were cough (83%), fever (41%), and rhinorrhea (40%) (F2). 110 (83%) were prescribed oseltamivir, with 24 (22%) receiving empiric therapy on day 0, and 63 (57%) prescribed on day 1 (F3). Among 109 patients with known symptom onset date, 34 (31%) were prescribed oseltamivir within 48 hours of symptom onset. 23 (17.3%) were prescribed antibiotics, 17 (74%) on day 0 (F3). Levofloxacin (26%), azithromycin (21%) and vancomycin (18%) were most commonly prescribed. Nine (6.8%) patients progressed to lower respiratory tract infection, 1 complicated by bacterial pneumonia. There were 11 (8.3%) influenza-related hospitalizations, 1 (0.7%) ICU admission, and no influenza-related deaths. Figure 1. Time From Symptom Onset to Date of First Clinical Encounter Figure 2. Symptoms Reported at First Clinical Encounter Figure 3. Time from First Clinical Encounter to Oseltamivir and Antibiotic Prescription Conclusion NAIs were frequently prescribed among cancer patients, but less than a third received treatment within 48 hours of symptom onset. Most were prescribed NAIs only after test results were available, while antibiotics were prescribed empirically. Delayed presentation to care is an obstacle to early NAI use; patient and provider education along with rapid diagnostics are needed to improve early NAI use among cancer patients with influenza. Disclosures Steven A. Pergam, MD, MPH, Chimerix, Inc (Scientific Research Study Investigator)Global Life Technologies, Inc. (Research Grant or Support)Merck & Co. (Scientific Research Study Investigator)Sanofi-Aventis (Other Financial or Material Support, Participate in clinical trial sponsored by NIAID (U01-AI132004); vaccines for this trial are provided by Sanofi-Aventis)

Background High morbidity and mortality has been observed with COVID-19 infection; however, there are limited data on clinical characteristics including exposures, coinfections, and antimicrobial use among cancer patients. We aimed to better characterize clinical features and outcomes in this population. Methods We conducted a retrospective chart review of consecutive patients at the Seattle Cancer Care Alliance diagnosed with SARS-CoV-2 infection by RT-PCR between February 28, 2020 and May 3, 2020. We obtained demographic and clinical data including coinfections, antimicrobial use and outcomes at 30 days after diagnosis. Results Of 60 patients reviewed, the median age was 62 years (range 22–98) and 43% were male. 34 (57%) patients had solid tumors and 16 (27%) hematologic malignancies. Breast (12%), colorectal (8%) and non-Hodgkin lymphoma (8%) were the most prevalent cancers. 34 (57%) had ≥ 2 comorbidities. The majority of identified exposures were from long-term care facilities (LTCF) (27%) or household contacts (25%) (Fig 1). The most common symptoms at diagnosis were cough (72%), fevers/chills (57%), shortness of breath (38%), nasal congestion/rhinorrhea (35%), and diarrhea (30%). 18 (31%) patients were prescribed at least one course of antibiotics within 30 days of diagnosis; antibiotics were prescribed to 54% of hospitalized patients (Fig 2). 6 (10%) had a documented bacterial infection; of these, 3 were respiratory coinfections. No viral or fungal copathogens were reported. 26 (43%) patients were hospitalized, 9 (15%) admitted to intensive care, and one (2%) required mechanical ventilation. 12 (20%) died within 30 days of diagnosis (Fig 3); of these, 10 (83%) had ≥ 2 comorbidities and 8 (67%) had LTCF exposure. Conclusion COVID-19 is associated with significant morbidity and mortality in cancer patients, particularly among older age groups with multiple comorbidities and those with LTCF exposure. More than half of cases appeared to acquire SARS-CoV-2 from LTCF or household exposures, indicating need for infection prevention and family/caregiver education. Despite few documented bacterial coinfections, antibiotic use within 30 days of diagnosis was common and likely empiric due to limited diagnostics in the era of COVID-19. Disclosures Steven A. Pergam, MD, MPH, Chimerix, Inc (Scientific Research Study Investigator)Global Life Technologies, Inc. (Research Grant or Support)Merck & Co. (Scientific Research Study Investigator)Sanofi-Aventis (Other Financial or Material Support, Participate in clinical trial sponsored by NIAID (U01-AI132004); vaccines for this trial are provided by Sanofi-Aventis) Alpana Waghmare, MD, Amazon (Grant/Research Support)Amazon (Employee, Shareholder)Ansun Biopharma (Scientific Research Study Investigator)Kyorin Pharmaceuticals (Advisor or Review Panel member)

Background Immunosuppressed cancer patients are at risk for morbidity and mortality from vaccine preventable diseases. Recent outbreaks and declining vaccination rates put cancer patients at increased risk for measles and mumps exposures. To assess the current status within our center, we measured measles and mumps seroprevalence among cancer patients. Methods Residual clinical plasma samples from patients seen at Seattle Cancer Care Alliance were collected between 8/11/2019 and 8/15/2019 and tested for measles and mumps IgG using ELISA (Genway Biotech); patients receiving intravenous immunoglobulin ≤16 weeks prior to collection date were excluded. Seroprevalence was calculated based on positive results; equivocal results were not considered protective. Demographic and clinical data were abstracted from medical records. Overall and subgroup seroprevalence were estimated with Wilson 95% confidence intervals (CI); Poisson regression with robust standard errors was used to compare subgroups and estimate prevalence ratios (PR). Results Of 1000 unique patients, 987 were eligible, with a median age of 61 years (range 2-97). More than half had a solid tumor (574 [58%]) while 376 (38%) had a hematologic malignancy (HM); 155 (16%) were hematopoietic cell transplant (HCT) recipients. The percentage of seropositive patients was 75% (95% confidence interval [CI]: 72%, 78%) for measles and 62% (95% CI: 59%, 65%) for mumps. Seropositivity was highest among older age groups, particularly those older than 63, who most likely have naturally acquired immunity (Figure 1-2). In multivariable analysis, patients aged 30-59 years were significantly less likely to be seropositive compared to patients ≥80 years of age. Patients with HM and those undergoing HCT were also less likely to be seropositive (Figure 3). Figure 1. Distribution of age at sample collection and measles antibody test results Figure 2. Measles and mumps seroprevalence by age Figure 3. Multivariable model estimates for measles and mumps seroprevalence Conclusion One-quarter of cancer patients tested did not have evidence of seroprotection for measles and mumps. Seronegative and equivocal responses were observed primarily among younger patients and those with hematologic malignancies. Deficits in protective antibody seen in this study are common among cancer patients and underscore the need for population/community-based efforts to increase herd immunity and protect vulnerable populations. Disclosures Helen Y. Chu, MD MPH, Cepheid (Grant/Research Support)Ellume (Grant/Research Support)Glaxo Smith Kline (Consultant)Merck (Consultant)Sanofi-Pasteur (Grant/Research Support) Steven A. Pergam, MD, MPH, Chimerix, Inc (Scientific Research Study Investigator)Global Life Technologies, Inc. (Research Grant or Support)Merck & Co. (Scientific Research Study Investigator)Sanofi-Aventis (Other Financial or Material Support, Participate in clinical trial sponsored by NIAID (U01-AI132004); vaccines for this trial are provided by Sanofi-Aventis)

Background Chimeric antigen receptor-modified T (CAR-T) cell immunotherapy for B cell hematologic malignancies results in prolonged B cell depletion. Little is known about the effects of CAR-T cell therapy on pre-existing pathogen-specific humoral immunity. Methods We conducted a prospective, cross-sectional study of children and adults treated with CD19- or BCMA-CAR-T cell therapy. Eligible patients were ≥ 6 months post-CAR-T cell infusion and in remission without subsequent chemoimmunotherapy. We measured total immunoglobulin G (IgG), pathogen-specific IgG levels for 12 vaccine-preventable infections, and B cell subsets from blood. Seroprotective antibody titers were based on standard thresholds. We described the proportion of patients with seroprotective titers and tested for associations between clinical factors and seroprotection using generalized estimating equations. Results We enrolled 65 patients who received CD19- (n=54) or BCMA- (n=11) CAR-T cell therapy. Seven patients were < 18 years old. Samples were collected a median of 20 months (range, 7–68) after CAR T cell infusion. Seroprotection to vaccine-preventable pathogens was generally comparable to the U.S. population (Fig 1) even though blood CD19+ B cell counts were low (< 20 cells/mm3) in 60% of patients. Among 30 patients without IgG replacement in the prior 16 weeks (4 half-lives of IgG), 27 (90%) had hypogammaglobulinemia. Despite this, these individuals had seroprotection to a median of 67% (IQR, 59%-73%) of tested pathogens (Fig 2A). The proportion of patients with seroprotection was lowest for mumps, hepatitis A and B, H. influenzae type B (Hib), S. pneumoniae, and B. pertussis. Patients receiving BCMA-CAR-T cells had seroprotection to fewer pathogens than those receiving CD19-CAR-T cells (Fig 2B), but the difference did not reach statistical significance (Fig 3). There were no significant differences by other variables. Figure 1. Proportion of CAR-T cell recipients with seroprotection to vaccine-preventable infections compared to the U.S. population, stratified by receipt of IgG replacement in the previous 16 weeks. Figure 2 A-B. Percentage of pathogens with seroprotective antibody titers among patients without IgG replacement in the previous 16 weeks. Figure 3. Association of clinical factors with seroprotection to vaccine-preventable infections among patients without IgG replacement in the previous 16 weeks (n=30) Conclusion Seroprotection for vaccine-preventable infections after CD19-CAR-T cell therapy was comparable to the general population. BCMA-CAR-T cell recipients may benefit most from replacement IgG. Vaccinations after CAR-T cell therapy should be considered and prioritized for S. pneumoniae, Hib, hepatitis viruses, and B. pertussis. Disclosures Justin J. Taylor, PhD, Vir Biotechnology (Grant/Research Support) Damian J. Green, MD, Cellectar Biosciences (Grant/Research Support)GSK (Advisor or Review Panel member)Juno Therapeutics (Grant/Research Support, Advisor or Review Panel member, Other Financial or Material Support, Royalities)Seattle Genetics (Grant/Research Support, Advisor or Review Panel member) Michael Boeckh, MD PhD, AlloVir (Consultant)EvrysBio (Advisor or Review Panel member, Other Financial or Material Support, share options)Gilead (Consultant, Grant/Research Support)GSK (Consultant)Helocyte (Advisor or Review Panel member, Shareholder)Lophius (Grant/Research Support)Merck (Consultant, Grant/Research Support)SymBio (Consultant)VirBio (Consultant, Grant/Research Support) David G. Maloney, MD, PhD, A2 Biotherapeutics (Consultant, Other Financial or Material Support, Stock Options)Bioline Rx (Consultant)Celgene (Consultant, Grant/Research Support)Gilead (Consultant)Juno Therapeutics (Consultant, Research Grant or Support, Other Financial or Material Support, four pending patents, not issued, licensed, no royalities, no licensees)Kite Pharma (Consultant, Grant/Research Support)Novartis (Consultant)Pharmacyclics (Consultant) Cameron J. Turtle, MBBS, PhD, Allogene (Other Financial or Material Support, Ad hoc advisory board (last 12 months))ArsenalBio (Advisor or Review Panel member, Other Financial or Material Support, Stock/options)AstraZeneca (Grant/Research Support, Other Financial or Material Support, Ad hoc advisory board (last 12 months))Caribou Biosciences (Advisor or Review Panel member, Other Financial or Material Support, Stock/options)Century Therapeutics (Advisor or Review Panel member)Eureka Therapeutics (Advisor or Review Panel member, Other Financial or Material Support, Stock/options)Juno Therapeutics (Grant/Research Support, Other Financial or Material Support, Patent: Licensed to Juno Therapeutics)Myeloid Therapeutics (Advisor or Review Panel member, Other Financial or Material Support, Stock/options)Nektar Therapeutics (Grant/Research Support, Other Financial or Material Support, Ad hoc advisory board (last 12 months))PACT Pharma (Other Financial or Material Support, Ad hoc advisory board (last 12 months))Precision Biosciences (Advisor or Review Panel member, Other Financial or Material Support, Stock/options)TCR2 Therapeutics (Grant/Research Support)T-CURX (Advisor or Review Panel member) Joshua A. Hill, MD, Allogene (Consultant)Allovir (Consultant)Gilead (Consultant)Karius (Grant/Research Support, Scientific Research Study Investigator)Takeda (Grant/Research Support, Scientific Research Study Investigator)

Background IDSA/SHEA guidelines recommend that antimicrobial stewardship programs support providers in antibiotic decisions for end of life care. Washington State Physician Orders for Life-Sustaining Treatment (POLST) forms allow patients to indicate antimicrobial use preferences. We sought to characterize antimicrobial use in the last 30 days of life for cancer patients by presence of a POLST and antimicrobial use preferences. Methods We performed a single-center, retrospective cohort study of cancer patient deaths from January 1, 2016 - June 30, 3018. Patient demographics, clinical characteristics, POLST, and antimicrobial use within 30 days before death were extracted from electronic records. To test for an association between POLST completed at least 30 days before death and inpatient antimicrobial days of therapy (DOT) in the 30 days before death, we used negative binomial models adjusted for age, sex, race, and service line (hematologic versus solid malignancy); model estimates are presented as incidence rate ratios (IRR) with 95% confidence intervals (CI) Results Of 1796 patients, 406 (23%) had a POLST. 177/406 (44%) were completed less than 30 days before death, and 58/177 (32.8%) specified limited antibiotic use; 40/177 (23%) did not specify any antimicrobial use preference (Fig 1). Of 1295 patients with at least 1 inpatient day in the 30 days before death, 1070 (83%) received at least 1 inpatient antimicrobial with median DOT of 1077 per 1000 inpatient days (Tab 1). There was no difference in DOT among patients with and without a POLST > /= 30 days before death (IRR 0.92, CI 0.77, 1.10). Patients with a POLST specifying limited antibiotic use had significantly lower inpatient IV antimicrobial DOT compared to those without a POLST (IRR 0.64, CI 0.42–0.97) (Fig 2). Figure 1. Classification of Patients by Presence of POLST, Timing, and Antimicrobial Preference Content of POLST. Numbers shown represent the number of patients (percentage). Full antibiotic use refers to the selection “Use antibiotics for prolongation of life.” Limited antibiotic use refers to the selection “Do not use antibiotics except when needed for symptom management.” Table 1: Antimicrobial use for all patients and by advance directive group Figure 2. Forest plot of model estimates, represented as incidence rate ratios (IRR) with 95% confidence intervals (CI), for associations between POLST antimicrobial specifications completed at least 30 days before death and inpatient antibiotic days of therapy (DOT) in the 30 days before death. Estimates represent comparisons between each POLST category and no POLST completed at least 30 days before death. Dots represent the IRR and brackets extend to the lower and upper limit of the 95% CI. Blue estimates are for the inpatient antibiotic DOT outcome and red estimates are for the inpatient IV antibiotic DOT outcome. Conclusion POLST completion is rare > /= 30 days before death, with few POLSTs specifying antimicrobial use. Compared to those with no POLST in this time frame, patients who indicated that antibiotics should be used only for symptom management received significantly fewer inpatient IV antimicrobials. Early discussion of advance directives including POLST with specification of antimicrobial use preferences may promote more thoughtful use of antimicrobials near the end of life in a compassionate, patient-centered way. Disclosures Steven A. Pergam, MD, MPH, Chimerix, Inc (Scientific Research Study Investigator)Global Life Technologies, Inc. (Research Grant or Support)Merck & Co. (Scientific Research Study Investigator)Sanofi-Aventis (Other Financial or Material Support, Participate in clinical trial sponsored by NIAID (U01-AI132004); vaccines for this trial are provided by Sanofi-Aventis)

Introduction Recent animal and human data suggest that antibiotic exposure prior to respiratory viral infection (RVI) increases risk of respiratory disease progression, presumably due to immunomodulatory effects of changes in the microbiota. However, few studies have identified the specific antibiotics that may be linked to respiratory viral disease progression. Objectives To investigate the associations between antibiotic exposure and disease progression of select RVIs after allogeneic hematopoietic cell transplantation (HCT). Methods We analyzed patients who underwent allogeneic HCT (4/2008-9/2018) and had their first RVI due to parainfluenza virus (PIV), respiratory syncytial virus (RSV), human metapneumovirus (MPV) or human rhinovirus (HRV) during the first 100 days after HCT. Antibiotic exposure in the 21 days before RVI onset was defined as A) any versus no use of specific antibiotics, and B) total antibiotic-days. Antibiotic-days was defined as cumulative sum of antibiotics received during each day in the specified time window. The probability of disease progression was estimated by cumulative incidence curves, treating death as a competing risk. We used Cox proportional hazard models to examine associations between antibiotic exposure and risk of disease progression to LRTD, adjusting for type of RVI, age at transplant, steroid use, lymphopenia and neutropenia before RVI onset. Data were censored at death, discharge, or 30 days post-RVI onset, whichever came first. Results We identified 469 HCT recipients (379 adults, 90 children) with first RVI (PIV 93, RSV 54, MPV 27, HRV 295), of which, 124 progressed to LRTD. Cumulative incidence of LRTD by tertiles of the total antibiotic-days (median 11, range 0-56) during the 21 days before onset of RVI is shown in Figure 1. In separate models, higher total antibiotic-days, use of antibiotics with broad anaerobic activity and use of cephalosporins with limited anaerobic activity were significantly associated with progression to LRTD. Figure 2 shows a forest plot of the adjusted hazard ratios between type of antibiotic exposure and progression to LRTD. Conclusion This study suggests that cumulative exposure to antibiotics prior to RVI is a risk factor for respiratory viral disease progression. Despite complex antibiotic use patterns in HCT recipients, our findings also suggest antibiotics of varying spectra may be associated with respiratory viral disease progression.

Highlights • This is one of the first studies on cervical cancer survival in a low-income country. • In Uganda, cervical cancer is often incompletely treated and survival remains poor. • HIV infection in this cohort was not associated with stage at diagnosis. • HIV was weakly associated with shorter survival., Our objective was to determine how HIV infection impacts cervical cancer stage at presentation and overall survival (OS) among Ugandan women. This was a prospective study of 149 women diagnosed with cervical cancer from 2013 to 2015 at the Uganda Cancer Institute. Poisson regression models were fit to calculate prevalence ratios (PR) for the association between HIV infection and late stage at cancer diagnosis. The association between HIV infection and OS after cervical cancer diagnosis was evaluated using Cox proportional hazards models. The cohort included 53 HIV-positive and 96 HIV-negative participants. Median age at diagnosis was 44 years for HIV-positive and 54 years for HIV-negative participants. Seventy-seven percent of HIV-positive participants received antiretroviral therapy. Median baseline CD4 count was 373 cells/mm3 for HIV-positive participants versus 926 cells/mm3 for HIV-negative participants. Thirty-two percent of HIV-positive participants were diagnosed with late stage cervical cancer (III-IV) versus 39% of HIV-negative participants. No association was found between late stage at cancer diagnosis and HIV infection (PR adjusted for age, parity and transport cost 1.0, 95%CI 0.6–1.8). Most women presenting for care received cancer treatment, though almost half who received radiotherapy did not complete treatment. The median OS was 13.7 months for HIV-positive participants and 24.3 months for HIV-negative participants. After adjusting for age and stage, HIV infection was weakly associated with OS (HR 1.3, 95%CI 0.8–2.2). In Uganda, cervical cancer is often incompletely treated and survival remains poor. HIV infection was not associated with cervical cancer stage at diagnosis, but may be weakly associated with shorter survival.

Background The influence of humoral immunity on the prevention of primary cytomegalovirus (CMV) infection after hematopoietic cell transplantation (HCT) is poorly understood. Methods To determine whether neutralizing antibodies (nAbs) against CMV pentameric complex (PC)-mediated epithelial cell entry decrease CMV infection after HCT, samples were analyzed from a randomized controlled trial of CMV intravenous immunoglobulin (IVIG) prophylaxis. Weekly serum from 61 CMV donor-positive/recipient-negative (D+/R−) HCT patients (33 control, 28 CMV IVIG) was tested using a PC-entry nAb assay and quantitative CMV polymerase chain reaction (PCR). Results There was a trend toward higher weekly PC-entry nAb titers (P = .07) and decreased CMV infection by PCR at viral load cutoffs of ≥1000 and ≥10 000 IU/mL in the CMV IVIG arm. High nAb titers were not significantly protective against CMV infection later after HCT in both study arms. Among CMV-infected patients, each log2 increase in nAb titer was associated with an average 0.2 log10 decrease in concurrent CMV viral load after infection (P = .001; adjusted for study arm). Conclusions This study provides initial support that CMV IVIG prophylaxis moderately enhances PC-entry nAB activity in D+/R− HCT recipients.

Background Patients with reported β-lactam antibiotic allergies (BLAs) are more likely to receive broad-spectrum antibiotics and experience adverse outcomes. Data describing antibiotic allergies among solid organ transplant (SOT) and hematopoietic cell transplant (HCT) recipients are limited. Methods We reviewed records of adult SOT or allogeneic HCT recipients from 1 January 2013 to 31 December 2017 to characterize reported antibiotic allergies at time of transplantation. Inpatient antibiotic use was examined for 100 days posttransplant. Incidence rate ratios (IRRs) comparing antibiotic use in BLA and non-BLA groups were calculated using multivariable negative binomial models for 2 metrics: days of therapy (DOT) per 1000 inpatient days and percentage of antibiotic exposure-days. Results Among 2153 SOT (65%) and HCT (35%) recipients, 634 (29%) reported any antibiotic allergy and 347 (16%) reported BLAs. Inpatient antibiotics were administered to 2020 (94%) patients during the first 100 days posttransplantation; average antibiotic exposure was 41% of inpatient-days (interquartile range, 16.7%–62.5%). BLA patients had significantly higher DOT for vancomycin (IRR, 1.4 [95% confidence interval {CI}, 1.2–1.7]; P < .001), clindamycin (IRR, 7.6 [95% CI, 2.2–32.4]; P = .001), and aztreonam in HCT (IRR, 9.7 [95% CI, 3.3–35.0]; P < .001), and fluoroquinolones in SOT (IRR, 2.9 [95% CI, 2.1–4.0]; P < .001); these findings were consistent when using percentage of antibiotic exposure-days. Conclusions Transplant recipients are frequently exposed to antibiotics and have a high prevalence of reported antibiotic allergies. Reported BLA was associated with greater use of β-lactam antibiotic alternatives. Pretransplant antibiotic allergy evaluation may optimize antibiotic use in this population.

PURPOSE "Endemic" Burkitt lymphoma (BL) is a common childhood cancer in Africa. Social and treatment factors may contribute to poor survival. With the aim of improving BL outcomes in Uganda, we undertook a comprehensive project (BL Project) that provided diagnostic support, access to standard chemotherapy, nutritional evaluations, and case management. We evaluated survival of children with BL in the context of the project. PATIENTS AND METHODS Patients followed by the BL Project who consented to research were enrolled in this study. Children with a pathology diagnosis consistent with BL were eligible. Data were collected prospectively. First-line chemotherapy generally consisted of six cycles of cyclophosphamide, vincristine, low-dose methotrexate (COM). We used Kaplan-Meier and Cox regression analyses to evaluate factors associated with overall survival (OS). RESULTS Between July 2012 and June 2017, 341 patients with suspected BL presented to the BL Project. One hundred eighty patients with a pathology-based diagnosis were included in this study. The median age was seven years (interquartile range, 5-9), 74% lived ≥100 km from the Uganda Cancer Institute, 61% had late-stage disease, 84% had ECOG performance status

Background Outpatient antibiotic prescribing for acute upper respiratory infections (URIs) is a high-priority target for antimicrobial stewardship that has not been described for cancer patients. Methods We conducted a retrospective cohort study of adult patients at an ambulatory cancer center with URI diagnoses from 1 October 2015 to 30 September 2016. We obtained antimicrobial prescribing, respiratory viral testing, and other clinical data at first encounter for the URI through day 14. We used generalized estimating equations to test associations of baseline factors with antibiotic prescribing. Results Of 341 charts reviewed, 251 (74%) patients were eligible for analysis. Nearly one-third (32%) of patients were prescribed antibiotics for URIs. Respiratory viruses were detected among 85 (75%) of 113 patients tested. Antibiotic prescribing (P = .001) and viral testing (P < .001) varied by clinical service. Sputum production or chest congestion was associated with higher risk of antibiotic prescribing (relative risk [RR], 2.3; 95% confidence interval [CI], 1.4–3.8; P < .001). Viral testing on day 0 was associated with lower risk of antibiotic prescribing (RR, 0.4; 95% CI 0.2–0.8; P = .01), though collinearity between viral testing and clinical service limited our ability to separate these effects on prescribing. Conclusions Nearly one-third of hematology–oncology outpatients were prescribed antibiotics for URIs, despite viral etiologies identified among 75% of those tested. Antibiotic prescribing was significantly lower among patients who received an initial respiratory viral test. The role of viral testing in antibiotic prescribing for URIs in outpatient oncology settings merits further study., Nearly one-third of hematology–oncology outpatients were prescribed antibiotics for upper respiratory infections (URIs), despite viral etiologies identified in 75% of patients tested. Antibiotic prescribing was significantly lower among patients who received a respiratory viral test and was not associated with subsequent upper respiratory infection-related healthcare visits.

Cytomegalovirus (CMV) infection occurs frequently in young children, who, when infected, are then a major source of transmission. Oral CMV shedding by 14 infants with primary infection was comprehensively characterized using quantitative polymerase chain reaction weekly for ≥9 months. Three phases of oral shedding were identified: expansion, transition, and clearance. Viral expansion occurred over a median of 7 weeks, with a median doubling time of 3 days. During the transition phase, expansion slowed over a median of 6 weeks before peak viral load was reached. Clearance was slow (22-day median half-life), and shedding did not resolve during observation for any infant. Mathematical modeling demonstrated that prolonged oral CMV expansion is explained by a low within-host reproduction number (median, 1.63) and a delayed immune response that only decreases the infected cell half-life by 44%. Thus, the prolonged oral CMV shedding observed during primary infection can be explained by slow viral expansion and inefficient immunologic control.

Background Following a meropenem shortage, we implemented a post-prescription review with feedback (PPRF) in November 2015 with mandatory infectious disease (ID) consultation for all meropenem and imipenem courses > 72 hours. Providers were made aware of the policy via an electronic alert at the time of ordering. Methods A retrospective study was conducted at the University of Washington Medical Center (UWMC) and Harborview Medical Center (HMC) to evaluate the impact of the policy on antimicrobial consumption and clinical outcomes pre- and post-intervention during a 6-year period. Antimicrobial use was tracked using days of therapy (DOT) per 1,000 patient-days, and data were analyzed by an interrupted time series. Results There were 4,066 and 2,552 patients in the pre- and post-intervention periods, respectively. Meropenem and imipenem use remained steady until the intervention, when a marked reduction in DOT/1,000 patient-days occurred at both hospitals (UWMC: percentage change -72.1%, (95% CI -76.6, -66.9), P < 0.001; HMC: percentage change -43.6%, (95% CI -59.9, -20.7), P = 0.001). Notably, although the intervention did not address antibiotic use until 72 hours after initiation, there was a significant decline in meropenem and imipenem initiation (“first starts”) in the post-intervention period, with a 64.9% reduction (95% CI 58.7, 70.2; P < 0.001) at UWMC and 44.7% reduction (95% CI 28.1, 57.4; P < 0.001) at HMC. Meropenem and Imipenem DOT (January 2013 – November 2019) Conclusion Mandatory ID consultation and PPRF for meropenem and imipenem beyond 72 hours resulted in a significant and sustained reduction in the use of these antibiotics and notably impacted their up-front usage. Disclosures All Authors: No reported disclosures

Purpose Optimal decision making regarding blood transfusion for patients with cancer requires appropriate knowledge of transfusion medicine among physicians. We assessed blood transfusion knowledge, attitudes, and reported practices among physicians working at Uganda Cancer Institute (UCI). Materials and Methods A cross-sectional self-administered survey of UCI physicians on their knowledge, attitudes, and practices regarding blood transfusion was conducted from June to September 2014. In consultation with transfusion medicine experts, 30 questions were developed, including 10 questions for each of the following three domains: knowledge, attitudes, and practices. For the knowledge domain, we created a knowledge score equal to the number of questions correctly answered out of 10. Results Of 31 physicians approached, 90% participated. The mean knowledge score was 5.3 (median, 5.5), and 32% correctly answered at least seven of 10 questions. Almost all (96%) understood the importance of proper patient identification before transfusion and indicated identification error as the most common cause of fatal transfusion reactions. More than 60% of physicians acknowledged they lacked knowledge and needed training in transfusion medicine. Most physicians reported sometimes changing their mind about whether to provide a patient with a transfusion on the basis of opinion of colleagues and sometimes administering unnecessary transfusions because of influence from others. Conclusion Although UCI physicians have some basic knowledge in transfusion, most reported gaps in their knowledge, and all expressed a need for additional education in the basics of blood transfusion. Transfusion training and evidence-based guidelines are needed to reduce inappropriate transfusions and improve patient care. Greater understanding of peer influence in transfusion decision making is required.

We examined vancomycin-resistant enterococci (VRE)-directed antimicrobial use and VRE bacteremia in a cohort of allogeneic hematopoietic cell transplantation patients from a center where VRE screening is standard prior to transplant. In this cohort, VRE bacteremia (VREB) was infrequent. In patients without VREB, colonized patients received VRE therapy more often than noncolonized patients.Infect Control Hosp Epidemiol2018;39:730–733

Background Antibiotic allergies impact the management of hematopoietic cell transplant (HCT) patients who are often prescribed antibiotics for infection prophylaxis and treatment. We evaluated the feasibility and outcomes of an antibiotic allergy evaluation program prior to allogeneic HCT. Methods In August 2017, we implemented a program to expedite allergy clinic referrals for adult allogeneic HCT candidates who reported an antibiotic allergy at their initial pre-transplant evaluation visit (PTEV). Allergy labels and clinical data including outcomes of allergy evaluation were prospectively collected for patients with PTEVs between 8/10/17 and November 15/18. The use of selected antibiotics was collected in the 100 days following HCT among patients with a reported β-lactam allergy (BLA). Choice of prophylactic agent for Pneumocystis jiroveci among patients with reported sulfa allergies was assessed among HCT recipients after engraftment. Results Of 276 allogeneic HCT candidates, 109 (39.5%) reported >= 1 antibiotic allergy (Table 1). Of the 109, 69 (63%) were referred for allergy evaluation; 83% (57/69) of those referred were evaluated at a median of 14 days after PTEV, and a median of 18 days before transplant. Among evaluated patients, 45 (79%) had >= 1 antibiotic allergy de-labeled including 74% (28/38) of those with BLA (Figure 1). Of the 10 patients whose BLAs could not be delabeled, 1 had a possible immediate IgE-mediated reaction, 5 had a delayed type IV hypersensitivity, and 4 had other reactions or required additional testing. Post-transplant antibiotic use among evaluated vs. nonevaluated patients reporting BLA is shown in Figure 2. Among 31 patients with reported sulfa allergies who underwent HCT, those who were evaluated received TMP-SMX rather than alternative prophylaxis more often (48%; 11/23) than those who were not evaluated (25%; 2/8). 10 (43%) of 23 evaluated patients were delabeled; 7 of 10 delabeled patients received TMP-SMX. Conclusion Antibiotic allergies are frequently reported among HCT candidates. Pre-transplant antibiotic allergy evaluation was feasible, led to de-labeling of the majority of reported allergies, and may alter antibiotic prescribing and increase the use of preferred agents following transplant. Disclosures All authors: No reported disclosures.

Background Patients with reported β-lactam antibiotic allergies (BLA) are more likely to receive broad-spectrum antibiotics and experience adverse outcomes. There are limited data on the burden of β-lactam and other antibiotic allergies among solid-organ transplant (SOT) and hematopoietic cell transplant (HCT) recipients. Methods We reviewed records of first-time adult SOT or allogeneic HCT recipients from January 1, 2013 to December 31, 2017 to characterize allergy labels at the time of transplant. Days of hospitalization and inpatient antibiotic use for pre-specified antimicrobials were collected for the first 100 days post-transplant, and incidence rate ratios (IRR) comparing BLA to non-BLA group were calculated using negative binomial models adjusted for transplant type, age, and diagnosis of cystic fibrosis as appropriate. If the adjusted estimates were significantly different for SOT and HCT recipients, separate models were presented. Results Among 2153 SOT (65%) and HCT (35%) recipients, 634 (29%) reported any antibiotic allergy and 347 (16%) reported BLAs (Figure 1). Of 634 patients with allergy labels, the most common were penicillins (40%), sulfa (29%), and cephalosporins (17%); 31% reported allergies to ≥2 classes of antibiotics. The most commonly reported reaction to β-lactams was rash (42%), followed by unknown (18%) and hives (17%). In a multivariable model (Table 1), patients with reported BLAs had significantly higher use of vancomycin (IRR 1.35 [95% CI 1.13, 1.60], P < 0.001) and significantly lower use of ampicillin-sulbactam (IRR 0.13 [0.05, 0.39], P < 0.001) and piperacillin–tazobactam (IRR 0.39 [0.25, 0.62], P < 0.001) compared with those without BLAs. For some antibiotics, the effect of BLA varied by SOT/HCT (Table 2). No significant differences in Clostridioides difficile infection or inpatient days were noted. Conclusion Transplant recipients have a high burden of reported antibiotic allergies, in particular BLAs. A BLA label was significantly associated with altered antibiotic prescribing in the early post-transplant period. Pre-transplant allergy evaluation may be helpful in directing antibiotic use following transplant as part of a comprehensive antibiotic stewardship program. Disclosures All authors: No reported disclosures.

BACKGROUND: Despite the high prevalence of herpes simplex virus type 2 (HSV-2) in sub-Saharan Africa the natural history of infection among Africans is not well characterized. We evaluated the frequency of genital HSV shedding in HIV-seropositive and HIV-seronegative men and women in Uganda. METHODS: Ninety-three HSV-2-seropositive Ugandan adults collected anogenital swab specimens for HSV DNA quantification by polymerase chain reaction 3 times daily for 6 weeks. RESULTS: HSV-2 was detected from 2484 of 11 283 swab specimens collected (22%) with a median quantity of 4.3 log10 HSV copies/mL (range 2.2-8.9 log10 HSV copies/mL). Genital lesions were reported on 749 of 3875 days (19%) and subclinical HSV shedding was detected from 1480 of 9113 swab specimens (16%) collected on days without lesions. Men had higher rates of total HSV shedding (relative risk [RR] 2.0 [95% confidence interval {CI} 1.3-2.9]; P < .001); subclinical shedding (RR 1.7 [95% CI 1.1-2.7]; P = .01) and genital lesions (RR 2.1 [95% CI 1.2-3.4]; P = .005) compared with women. No differences in shedding rates or lesion frequency were observed based on HIV serostatus. CONCLUSIONS: HSV-2 shedding frequency and quantity are high among HSV-2-seropositive adults in sub-Saharan Africa including persons with and those without HIV infection. Shedding rates were particularly high among men which may contribute to the high prevalence of HSV-2 and early acquisition among African women. (c) The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions e-mail journals.permissions@oup.com.

Background The introduction of antiretroviral therapy (ART) in the United States and Europe has led to changes in the incidence of cancers among HIV-infected persons, including dramatic decreases in Kaposi sarcoma and non-Hodgkin lymphoma, and increases in Hodgkin lymphoma, liver, and anogenital malignancies. We sought to evaluate whether increasing availability of ART is associated with changing cancer incidence in Uganda. Methods Incident cases of 10 malignancies were identified from Kampala Cancer Registry from 1999 to 2008. ART coverage rates for Uganda were abstracted from the Joint United Nations Program on HIV/AIDS reports. Negative binomial and Poisson regression modeled the association between ART coverage and age-adjusted cancer incidence. Results ART coverage in Uganda increased from 0% to 43% from 1999 to 2008. With each 10% increase in ART coverage, incidence of Kaposi sarcoma decreased by 5% [incidence rate ratio (IRR) = 0.95, 95% confidence interval: 0.91 to 0.99, P = 0.02] and stomach cancer decreased by 13% [IRR = 0.87 (95% CI: 0.80 to 0.95), P = 0.002]. Conversely, incidence of non-Hodgkin lymphoma increased by 6% [IRR = 1.06 (95% CI: 1 to 1.12), P = 0.05], liver cancer by 12% [IRR = 1.12 (95% CI: 1.04 to 1.21), P = 0.002], prostate cancer by 5% [IRR = 1.05 (95% CI: 1 to 1.10), P = 0.05], and breast cancer by 5% [IRR = 1.05 (95% CI: 1 to 1.11), P = 0.05]. ART coverage was not associated with incidence of invasive cervical cancer, lung, colon, and Hodgkin disease. These findings were similar when restricted to histologically confirmed cases. Conclusions Our findings suggest that AIDS-defining malignancies and other malignancies are likely to remain significant public health burdens in sub-Saharan Africa even as ART availability increases.

American Indians and Alaska Natives (AI/ANs) die from chronic liver disease at high rates, but little data exist on the etiology of liver disease in AI/ANs. Adult participants from a tribal health clinic in the Pacific Northwest completed an alcohol consumption survey and underwent laboratory testing, and anthropometric measurements. Participants with abnormal serum alanine aminotransferase (ALT) levels, positive hepatitis B surface antigen, or hepatitis C antibody were invited for follow-up visit. Then, they received a limited liver ultrasound, additional liver function tests, and confirmatory hepatitis tests. Among 71 participants, 26 (37%) had sustained elevation of ALT over six months. Two patients (8%) had chronic hepatitis C virus and 19 (73%) had ultrasonographic steatosis suggesting nonalcoholic fatty liver disease (NAFLD). Elevated aminotransferase levels were common, with NAFLD and hepatitis C accounting for most cases. Few participants were aware of their liver condition, indicating the need for increased awareness, screening, and intervention.

Human herpesviruses (HHV) establish lifelong latent infection and are transmitted primarily via shedding at mucosal surfaces. Each HHV causes a unique spectrum of disease depending on the infected individual’s age and immunity. We collected weekly oral swabs from young children and mothers in 32 Ugandan households for a median of one year. We characterized kinetics of oral shedding during primary and chronic infection for each virus. Cytomegalovirus (CMV), Epstein-Barr virus (EBV), and HHV-6 were shed at high rates following primary infection. The rate of oral herpes simplex virus (HSV) shedding was lower overall, and children and mothers with chronic HSV infection had lower shedding rates than children with primary infection. CMV shedding rate and viral load were higher in children with primary infection compared to children with chronic infection, and even lower in mothers with chronic infection. HHV-6 shedding rate and viral load were similar between children with primary or chronic infection, but lower in mothers. EBV shedding rate and quantity decreased less dramatically in mothers versus children, with HIV-positive mothers shedding at a higher rate than HIV-negative mothers. Each HHV has a distinct pattern of oral shedding which depends partially on the age and immune status of the host.