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BACKGROUND Risk factors, virological parameters, and outcomes associated with HHV-6 viremia in high-risk donor CMV-seropositive and recipient CMV-seronegative (D+R-) liver transplant recipients in the current era are incompletely defined. METHODS The study population consisted of patients in the preemptive therapy (PET) arm of a randomized, controlled trial of PET versus valganciclovir prophylaxis for CMV prevention in D+R- liver transplant recipients. Weekly blood samples through 100 d in the PET group were tested for HHV-6 viremia using a real-time quantitative polymerase chain reaction. Assessments included virological characteristics and relationship with CMV, risk factors, and impact of HHV-6 viremia with outcomes through 12 mo posttransplant. RESULTS HHV-6 viremia at any level developed in 42% (40 of 96). Older patient age (P = 0.03), longer hospitalization (P = 0.015), and ICU stay at transplantation (P = 0.029) were significantly associated with high-grade viremia. Concurrent HHV-6 and CMV viremia was associated with earlier onset of HHV-6 viremia (P = 0.004), higher HHV-6 area under the curve (P = 0.043), and higher peak HHV-6 viral load (P = 0.006) versus HHV-6 viremia alone. High-grade viremia was independently associated with biopsy-proven rejection within 12 mo (P = 0.045) posttransplant. CONCLUSIONS Among D+R- liver transplant recipients receiving valganciclovir as PET, high-grade HHV-6 viremia was associated with increased age and critical illness in ICU at time of transplant and was independently associated with allograft rejection.

Background The relative costs of preemptive therapy (PET) or prophylaxis for the prevention of cytomegalovirus (CMV) disease in high-risk donor CMV-seropositive/recipient-seronegative (D+/R−) liver transplant recipients have not been assessed in the context of a randomized trial. Methods A decision tree model was constructed based on the probability of outcomes in a randomized controlled trial that compared valganciclovir as PET or prophylaxis for 100 days in 205 D+/R− liver transplant recipients. Itemized costs for each site were obtained from a federal cost transparency database. Total costs included costs of implementation of the strategy and CMV disease treatment-related costs. Net cost per patient was estimated from the decision tree for each strategy. Results PET was associated with a 10% lower absolute rate of CMV disease (9% vs 19%). The cost of treating a case of CMV disease in our patients was $88 190. Considering cost of implementation of strategy and treatment-related cost for CMV disease, the net cost-savings per patient associated with PET was $8707 compared to prophylaxis. PET remained cost-effective across a range of assumptions (varying costs of monitoring and treatment, and rates of disease). Conclusions PET is the dominant CMV prevention strategy in that it was associated with lower rates of CMV disease and lower overall costs compared to prophylaxis in D+/R− liver transplant recipients. Costs were driven primarily by more hospitalizations and higher CMV disease–associated costs due to delayed onset postprophylaxis disease in the prophylaxis group.

Cytomegalovirus (CMV) reactivation has been described in adults with critical illness caused by diverse etiologies, especially severe sepsis, and observational studies have linked CMV reactivation with worse clinical outcomes in this setting. In this study, we review observational clinical data linking development of CMV reactivation with worse outcomes in patients in the intensive care unit, discuss potential biologically plausible mechanisms for a causal association, and summarize results of initial interventional trials that examined the effects of CMV prevention. These data, taken together, highlight the need for a randomized, placebo-controlled efficacy trial (1) to definitively determine whether prevention of CMV reactivation improves clinical outcomes of patients with critical illness and (2) to define the underlying mechanism(s).

BK polyomavirus (BKPyV) has been associated with hemorrhagic cystitis (HC) after allogeneic hematopoietic cell transplantation (HCT), but the natural history of HC and factors associated with the clinical course are incompletely understood. We retrospectively analyzed allogeneic HCT patients transplanted from 2007-2017 who presented after platelet engraftment or after day 28 post-HCT with BKPyV-associated HC (BKPyV-HC), which was defined as a positive urine BKPyV PCR, ≥1 plasma BKPyV viral load result, and macroscopic hematuria (Bedi grade ≥2). Factors associated with resolution of macroscopic hematuria and resolution of all cystitis symptoms within 90 days after HC diagnosis were investigated in multivariable models. In 128 patients with BKPyV-HC, the median times from diagnosis to resolution of all symptoms, macroscopic hematuria, and urinary clots (present in 55% [71/128]) were 24 days (15-44), 17 days (10-30), and 14 days (5-26), respectively. Ninety percent of patients had BKPyV viremia at the onset of HC with a median viral load of 1850 copies/mL (interquartile range, 240-8550). In multivariable models, high plasma viral load (≥10 000 copies/mL) and cytopenias at the beginning of BKPyV-HC were significantly associated with longer macroscopic hematuria and cystitis symptoms. Use of cidofovir was not associated with shorter duration of illness. In conclusion, BKPyV-HC after allogeneic HCT is characterized by prolonged and severe symptoms and requires improved management strategies. High-grade viremia and cytopenias were associated with a longer duration of BKPyV-associated HC. Accurate descriptions of disease and factors associated with prolonged recovery will inform end points of future clinical trials.

Lung transplant recipients (LTR) with Covid-19 may have higher mortality than non-lung solid organ transplant recipients (SOTR), but direct comparisons are limited. Risk factors for mortality specifically in LTR have not been explored. We performed a multicenter cohort study of adult SOTR with Covid-19 to compare mortality by 28-days between hospitalized LTR and non-lung SOTR. Multivariable logistic regression models were used to assess comorbidity-adjusted mortality among LTR vs. non-lung SOTR and to determine risk factors for death in LTR. Of 1,616 SOTR with Covid-19, 1,051 (65%) were hospitalized including 117/159 (74%) LTR and 934/1457 (64%) non-lung SOTR (p=0.02). Mortality was higher among LTR compared to non-lung SOTR (24% vs. 16%, respectively, p=0.035) and lung transplant was independently associated with death after adjusting for age and comorbidities (aOR 1.7, 95% CI 1.0-2.6, p=0.05). Among LTR, independent risk factors for mortality included single lung transplant (aOR 2.8, 95% CI 1.0-7.7, p=0.04) and chronic lung allograft dysfunction (aOR 3.6, 95% CI 1.0-12.4, p=0.05), but not age >65 years, heart failure, or obesity. Among SOTR hospitalized for Covid-19, LTR had higher mortality than non-lung SOTR. In LTR, single lung transplant and chronic allograft dysfunction were independently associated with mortality.

Few options are available for cytomegalovirus (CMV) treatment in transplant recipients resistant, refractory, or intolerant to approved agents. Letermovir (LET) is approved for prophylaxis in hematopoietic cell transplant (HCT) recipients, but little is known about efficacy in CMV infection. We conducted an observational study to determine the patterns of use and outcome of LET treatment of CMV infection in transplant recipients.Patients who received LET for treatment of CMV infection were identified at 13 transplant centers. Demographic and outcome data were collected.Twenty-seven solid organ and 21 HCT recipients (one dual) from 13 medical centers were included. Forty-five of 47 (94%) were treated with other agents prior to LET, and 57% had a history of prior CMV disease. Seventy-seven percent were intolerant to other antivirals; 32% were started on LET because of resistance concerns. Among 37 patients with viral load 1000 international units (IU)/ml at LET initiation, two experienced 1 log rise in viral load by week 12, and no deaths were attributed to CMV. Ten patients had viral load 1000 IU/ml at LET initiation, and six of 10 (60%) had a CMV viral load 1000 IU/ml at completion of therapy or last known value. LET was discontinued in two patients for an adverse event.Patients treated with LET with viral load 1000 IU/ml had good virologic outcomes. Outcomes were mixed when LET was initiated at higher viral loads. Further studies on combination therapy or alternative LET dosing are needed.

The differential impact of preemptive therapy (PET) and antiviral prophylaxis (AP) on development of cytomegalovirus (CMV)–specific neutralizing antibody (nAb) and T-cell responses have not previously been directly compared in high-risk donor-seropositive/recipient-seronegative (D+R−) organ transplant recipients. We prospectively assessed T-cell and nAb responses 3 months after transplantation in cohorts of high-risk D+R− liver transplant recipients who received either PET (n = 15) or AP (n = 25) and a control group of CMV-seropositive transplant recipients (R+) (AP; n = 24). CMV phosphoprotein 65 (pp65)– and immediate early protein 1–specific multifunctional T-cell responses were determined by means of intracellular cytokine staining and nAbs against BADrUL131-Y4 CMV in adult retinal pigment epithelial cell line-19 human epithelial cells; nAbs were detected in 8 of 12 (67%) in the PET group, none of 17 in the AP group, and 20 of 22 (91%) in the R+ group. Multifunctional CD8 and CD4 T-cell responses to pp65 were generally similar between PET and R+ groups, and lower for the AP group; multifunctional CD4 responses were similar across all groups. Among D+R− liver transplant recipients, PET was associated with the development of greater nAb and multifunctional CD8 T-cell responses compared with AP, providing a potential mechanism to explain the relative protection against late-onset disease with PET. Future studies are needed to define specific immune parameters predictive of late-onset CMV disease with AP.

Cytomegalovirus (CMV) reactivation occurs in roughly one-third of immunocompetent patients during critical illness, and is associated with worse outcomes. These outcomes have prompted consideration of early antiviral prophylaxis, but two-third of patients would receive unnecessary treatment. Tissue viral load has been associated with risk of reactivation in murine models, and recent work has suggested a relationship between immune responses to CMV and underlying viral load. We, therefore, sought to confirm the hypothesis that serum CMV-specific immunoglobulin G (IgG) correlates with tissue viral load, and might be used to predict the risk of reactivation during critical illness. We confirm that there is a good correlation between tissue viral load and serum CMV-specific IgG after laboratory infection of inbred mice. Further, we show that naturally infected outbred hosts have variable tissue viral DNA loads that do not correlate well with serum IgG. Perhaps as a consequence, CMV-specific IgG was not predictive of reactivation events in immunocompetent humans. When reactivation did occur, those with the lowest IgG levels had longer durations of reactivation, but IgG quartiles were not associated with differing peak DNAemia. Together our data suggest that CMV-specific IgG titers diverge from tissue viral loads in outbred immunocompetent hosts, and their importance for the control of reactivation events remains unclear.

Background Detailed cytomegalovirus (CMV) kinetics in donor CMV-seropositive, recipient CMV-seronegative (D+/R–) transplant recipients receiving preemptive therapy (PET) have not been fully defined. Methods The study population consisted of the PET arm of a randomized CMV prevention trial in D+/R– liver transplant recipients. CMV DNA polymerase chain reaction (PCR) assays were performed weekly for 100 days using a sensitive assay. Viral load and clinical parameters were compared for patients with or without high-level increase (defined as higher than the group median log10 increase in viral load from baseline after PET initiation). Results Among 79 patients, 93.6% (74/79) developed an increase from baseline viral loads of median 120 IU/mL to 3350 IU/mL; 25.7% (19/74) of the patients had peak levels >10 000 IU/mL. None of the patients with rise in viral load underwent testing for CMV resistance, and viremia resolved with PET with valganciclovir. Patients with high-level increase in viral load had a significantly lower rate of recurrent viremia than those without such increase (16/40 [40%] vs 28/39 [71.8%], respectively; P = .004). Conclusions A majority of D+/R– recipients had a marked increase in viral load after initiation of PET before resolution of viremia. This phenomenon is associated with lower rates of subsequent recurrent viremia and does not necessarily imply antiviral resistance.

Hosts with compromised or naive immune systems, such as individuals living with HIV/AIDS, transplant recipients, and fetuses, are at the highest risk for complications from cytomegalovirus (CMV) infection. Despite substantial progress in prevention, diagnostics, and treatment, CMV continues to negatively impact both solid-organ transplant (SOT) and hematologic cell transplant (HCT) recipients. In this article, we summarize important developments in the field over the past 10 years and highlight new approaches and remaining challenges to the optimal control of CMV infection and disease in transplant settings.

Background. Risk factors for cytomegalovirus (CMV) viremia in CMV seropositive liver transplant recipients are incompletely defined and have focused primarily on recipient factors. We hypothesized that active CMV replication (CMV viremia) in seropositive donors might increase the risk for CMV viremia in recipients, as reported for other viruses in organ transplantation. Methods. From January 3, 2009, to July 27, 2015, stored plasma from consecutive CMV seropositive liver donors was retrospectively tested for CMV viremia by PCR. From April 20, 2012, to July 27, 2015, CMV seropositive recipients of a liver transplant from the donors during this time period received preemptive therapy for CMV prevention (valganciclovir therapy for CMV viremia ≥250 IU/mL). The association of recipient factors and donor CMV viremia with viremia in recipients was assessed. Results. Among 317 CMV-seropositive donors, CMV viremia was detected in 11 (3.5%) and was associated with longer time to collection after admission and bacteremia. Among 115 CMV-seropositive liver recipients, 5 (4.3%) received an organ from a donor with CMV viremia. Donor CMV viremia was independently associated with higher incidence of CMV viremia ≥250 IU/mL and shorter time to onset of CMV viremia ≥250 IU/mL in recipients: 4 (80%) versus 26 (23.6%), P = 0.02, and hazard ratio 8.55 (2.60–28.10), P = 0.003, respectively. Conclusion. Donor CMV reactivation is associated with CMV viremia in seropositive orthotopic liver transplant recipients receiving preemptive therapy, identifying a novel potential risk factor for CMV infection in seropositive liver transplant recipients. Future studies should independently validate and assess these findings in other organ transplant settings.

Blood culture (BC) often fails to detect bloodstream microorganisms in sepsis. However, molecular diagnostics hold great potential. The molecular method PCR/electrospray ionization-mass spectrometry (PCR/ESI-MS) can detect DNA from hundreds of different microorganisms in whole blood. The aim of the present study was to evaluate the performance of this method in a multicenter study including 16 teaching hospitals in the United States (n = 13) and Europe (n = 3)., Blood culture (BC) often fails to detect bloodstream microorganisms in sepsis. However, molecular diagnostics hold great potential. The molecular method PCR/electrospray ionization-mass spectrometry (PCR/ESI-MS) can detect DNA from hundreds of different microorganisms in whole blood. The aim of the present study was to evaluate the performance of this method in a multicenter study including 16 teaching hospitals in the United States (n = 13) and Europe (n = 3). First, on testing of 2,754 contrived whole blood samples, with or without spiked microorganisms, PCR/ESI-MS produced 99.1% true-positive and 97.2% true-negative results. Second, among 1,460 patients with suspected sepsis (sepsis-2 definition), BC and PCR/ESI-MS on whole blood were positive in 14.6% and 25.6% of cases, respectively, with the following result combinations: BC positive and PCR/ESI-MS negative, 4.3%; BC positive and PCR/ESI-MS positive, 10.3%; BC negative and PCR/ESI-MS positive, 15.3%; and BC negative and PCR/ESI-MS negative, 70.1%. Compared with BC, PCR/ESI-MS showed the following sensitivities (coagulase-negative staphylococci not included): Gram-positive bacteria, 58%; Gram-negative bacteria, 78%; and Candida species, 83%. The specificities were >94% for all individual species. Patients who had received prior antimicrobial medications (n = 603) had significantly higher PCR/ESI-MS positivity rates than patients without prior antimicrobial treatment—31% versus 22% (P

Background The risk factors for development of viremia in high-risk donor cytomegalovirus (CMV)-seropositive and recipient CMV-seronegative (D+R−) transplant recipients are incompletely defined. Methods The study population comprised patients in the preemptive therapy (PET) arm of a randomized, controlled trial of PET versus prophylaxis using valganciclovir in D+R− liver transplant recipients. Weekly surveillance monitoring for viremia for 100 days was performed using a sensitive CMV-DNA polymerase chain reaction assays. Risk factors for viremia and time to onset (≤4 vs >4 weeks) of viremia were examined using logistic regression models. Results Viremia developed in 84% (79/94) of recipients and older donor age was the only independent factor associated with viremia (odds ratio, 2.20 for each quartile increase in donor age; 95% confidence interval [CI], 1.07–4.52; P = .031). Recipients who developed early-onset viremia (within 4 weeks) also had significantly older donors than those with later-onset viremia (difference in age 10.1 years; 95% CI, 2–19; P = .03). Conclusions Older donor age was an independent predictor of viremia and earlier-onset of viremia in D+R− liver transplant recipients. Future studies should assess the mechanistic links underlying this novel association. Clinical Trial Registration NCT01552369.

We performed multivariable analysis of potential risk factors (including cytomegalovirus [CMV] reactivation) for clinical outcomes by day 28 (death or continued hospitalization, ventilator-free days, intensive care unit (ICU)-free days, hospital-free days) from pooled cohorts of 2 previous prospective studies of CMV-seropositive adults with sepsis. CMV reactivation at any level, >100 IU/mL, >1000 IU/mL, peak viral load, and area under the curve were independently associated with the clinical outcomes. We identified the potential effect size of CMV on outcomes that could be used as end points for future interventional trials of CMV prevention using antiviral prophylaxis in ICU patients with sepsis.

With the rapidly expanding pandemic of SARS-CoV-2, there is concern that solid organ transplant recipients will be particularly vulnerable to infection and may experience a more severe clinical course. We report four cases of COVID-19 in solid organ transplant recipients including recipients of kidney, liver, lung, and heart transplants. We describe each patient's medical history including transplantation history, their clinical presentation and workup, and their course from diagnosis to either hospital discharge or to improvement in symptoms. These reports demonstrate a range of symptoms, clinical severity, and disease course in solid organ transplant recipients with COVID-19, including two hospitalized patients and two patients managed entirely in the outpatient setting.

BACKGROUND Exosomes isolated from plasma of lung transplant recipients (LTxRs) with bronchiolitis obliterans syndrome (BOS) contain human leukocyte antigens and lung self-antigens (SAgs), K-alpha 1 tubulin (Kα1T) and collagen type V (Col-V). The aim was to determine the use of circulating exosomes with lung SAgs as a biomarker for BOS. METHODS Circulating exosomes were isolated retrospectively from plasma from LTxRs at diagnosis of BOS and at 6 and 12 months before the diagnosis (n = 41) and from stable time-matched controls (n = 30) at 2 transplant centers by ultracentrifugation. Exosomes were validated using Nanosight, and lung SAgs (Kα1T and Col-V) were detected by immunoblot and semiquantitated using ImageJ software. RESULTS Circulating exosomes from BOS and stable LTxRs demonstrated 61- to 181-nm vesicles with markers Alix and CD9. Exosomes from LTxRs with BOS (n = 21) showed increased levels of lung SAgs compared with stable (n = 10). A validation study using 2 separate cohorts of LTxRs with BOS and stable time-matched controls from 2 centers also demonstrated significantly increased lung SAgs–containing exosomes at 6 and 12 months before BOS. CONCLUSIONS Circulating exosomes isolated from LTxRs with BOS demonstrated increased levels of lung SAgs (Kα1T and Col-V) 12 months before the diagnosis (100% specificity and 90% sensitivity), indicating that circulating exosomes with lung SAgs can be used as a non-invasive biomarker for identifying LTxRs at risk for BOS.

IMPORTANCE: Despite the use of a cytomegalovirus (CMV) prevention strategy of antiviral prophylaxis for high-risk CMV-seronegative liver transplant recipients with seropositive donors, high rates of delayed-onset postprophylaxis CMV disease occur. An alternate approach, preemptive therapy (initiation of antiviral therapy for early asymptomatic CMV viremia detected by surveillance testing), has not previously been directly compared with antiviral prophylaxis in these patients. OBJECTIVE: To compare preemptive therapy with antiviral prophylaxis in CMV-seronegative liver transplant recipients with seropositive donors for the prevention of CMV disease. DESIGN, SETTING, AND PARTICIPANTS: Randomized clinical trial of preemptive therapy vs antiviral prophylaxis in 205 CMV-seronegative liver transplant recipients with seropositive donors aged older than 18 years. The trial was conducted at 6 academic transplant centers in the United States between October 2012 and June 2017, with last follow-up in June 2018. INTERVENTIONS: Patients were randomized 1:1 to receive either preemptive therapy (valganciclovir, 900 mg, twice daily until 2 consecutive negative tests a week apart) for viremia detected by weekly plasma CMV polymerase chain reaction for 100 days (n = 100) or valganciclovir, 900 mg, daily for 100 days as antiviral prophylaxis (n = 105). MAIN OUTCOMES AND MEASURES: The primary outcome was incidence of CMV disease by 12 months, defined as CMV syndrome (CMV viremia and clinical or laboratory findings) or end-organ disease. Secondary outcomes included acute allograft rejection, opportunistic infections, graft and patient survival, and neutropenia. RESULTS: Among 205 patients who were randomized (mean age, 55 years; 62 women [30%]), all 205 (100%) completed the trial. The incidence of CMV disease was significantly lower with preemptive therapy than antiviral prophylaxis (9% [9/100] vs 19% [20/105]; difference, 10% [95% CI, 0.5% to 19.6%]; P = .04]). The incidence of allograft rejection (28% vs 25%; difference, 3% [95% CI, −9% to 15%]), opportunistic infections (25% vs 27%; difference, 2% [95% CI, −14% to 10%]), graft loss (2% vs 2%; difference

BACKGROUND: Few data support current guideline recommendations for 6 months over 3 months of antiviral prophylaxis for cytomegalovirus (CMV) disease prevention in donor seropositive/recipient seronegative (D+R-) heart transplant recipients (HTR). METHODS: We retrospectively assessed CMV disease and clinical outcomes in 310 adult HTR between 7/5/2005 – 12/30/2016 at a single center. Valganciclovir (VGCV) prophylaxis was given for 3 months in recipient seropositive (R+) and for 3 to 6 months in D+R- groups. A multivariable logistic model evaluated risk factors for CMV disease, with use of inverse probability weighting to correct for confounding. A nested matched cohort study within D+R- HTR was performed to assess CMV disease-associated morbidity. Chi-square and Mann-Whitney tests compared categorical and continuous variables, with p < 0.05 considered significant. RESULTS: The incidence of CMV disease among all, D+R-, and R+ groups was 8.7% (27/310), 26.5% (22/83), and 2.8% (5/180), respectively, and included syndrome in 22.2% (6/27) and end-organ involvement in 77.8% (21/27). In multivariable models, longer prophylaxis duration was not associated with reduced risk for CMV disease when assessed either as a continuous (p=0.28) or categorical (3 vs 6 months) variable (p=0.19). CMV disease in D+R- HTR was associated with higher rates of hospitalization (87.5% [14/16] vs 6.3% [1/16], p

Kidney Donor Risk Index (KDRI) introduced in 2009 included hepatitis C serologic but not viremic status of the donors. With nucleic acid amplification testing (NAT) now being mandatory, further evaluation of these donors is possible. We conducted a retrospective matched case-control analysis of adult deceased donor kidney transplants performed between December 5, 2014 to December 31, 2016 with the KDRI score and hepatitis C virus antibody (HCV Ab) and NAT testing status obtained from the United Network for Organ Sharing database. The 205 aviremic HCV Ab+ NAT - kidney transplants were compared to KDRI matched control kidneys that were HCV Ab-NAT-. The aviremic HCV kidneys were recovered from donors who were significantly younger, more likely to be white, and less likely to have hypertension and diabetes. The majority of the recipients of the aviremic HCV kidneys when compared to matched controls were HCV positive: 90.2% vs 4.3%. The recipients were significantly older, were on dialysis for a shorter time, and were transplanted sooner. The graft survival of aviremic HCV kidneys was similar (P .08). If the HCV status of the aviremic kidneys was assumed to be negative, 122 more kidneys could have been allocated to patients with estimated posttransplant survival20. Seven kidneys would no longer have Kidney Donor Profile Index85%. Further policies might consider these findings to appropriately allocate these kidneys.

BACKGROUND The number of Public Health Service increased-risk organ donors (PHS IRD) is growing, largely from an increase in intravenous drug use overdoses due to the current opioid epidemic. MATERIAL AND METHODS We conducted a retrospective case series review using our single-center data. We reviewed 82 PHS IRD kidney transplant offers between 2015 and 2017, 20 of which were declined. We reviewed outcomes of patients who declined vs. accepted PHS IRD offers. We studied the effect of education on these patients' willingness to consider another PHS IRD. RESULTS Twenty patients declined PHS IRD over a 2-year period. They waited on average 9 months for another transplant, and tended to be transplanted with a higher-KDPI kidney than the one originally offered. Patients who declined PHS IRD were more likely to be predialysis, women, and Asian American, and to require an interpreter. Ninety-two percent of patients who received education on PHS IRD after declining an offer stated that they would consider another PHS IRD offer in the future. Four of these patients received a PHS IRD transplant. CONCLUSIONS Our results suggest that education of patients may have a positive impact on patient attitudes toward PHS IRD.

Summary Polyomavirus nephropathy (PVN) is a major complication of kidney transplantation. Most reports describe polyomavirus viremia either precedes or is detectable at the time of diagnosis of PVN. This association is the basis of current screening recommendations. We retrospectively reviewed the PCR results of blood and urine samples from 29 kidney transplant recipients with biopsy-proven PVN. Biopsies were performed for a rise in serum creatinine or persistent high-level BK viruria. All biopsies showed polyoma virus large T-antigen expression in tubular epithelium using immunohistochemistry. All had viruria preceding or at the time of biopsy (range, 5.2 × 104 to >25 × 106 BKV DNA copies/ml). Twenty (69%) had viremia ranging from 2.5 × 103 to 4.3 × 106 copies/ml at the time of the biopsy. Via blood BK PCR assay, nine (31%) had no BK viremia detected either preceding or at the time of the biopsy. In five recipients where sufficient specimen permitted, additional plasma BK assessment revealed positive detection of viremia. A comparative analysis of assays from two centres was performed with spiked samples. BK DNA may not be detected in the blood of some kidney transplant recipients with histologically confirmed PVN. This may reflect limitation of whole blood as opposed to plasma-based BK DNA assessment.

We describe a case of acute liver failure and myopericarditis due to herpes simplex virus–1 (HSV-1) in an immunocompetent adult. We estimate that, at the height of viremia, the patient contained a quantity of HSV-1 virions approaching that of human cells. The patient recovered with acyclovir that was dose-adjusted for neurotoxicity and developed a vigorous anti-HSV-1 T-cell response.

Background Hematopoietic-cell transplant (HCT) recipients are at risk for severe respiratory syncytial virus (RSV) infection. We evaluated the RSV fusion inhibitor presatovir in a randomized, double-blind, Phase II trial in HCT recipients with RSV upper respiratory tract infections. Methods Patients were stratified by lymphopenia (, Presatovir treatment was safe but did not improve viral or clinical outcomes in hematopoietic-cell transplant recipients with respiratory syncytial virus upper respiratory tract infections. Exploratory analyses suggest clinical benefit in hematopoietic-cell transplant patients with lymphopenia at presentation.

These updated guidelines from the American Society of Transplantation Infectious Diseases Community of Practice review the diagnosis, prevention, and management of varicella zoster virus (VZV) in the pre- and post-transplant period. Primary varicella is an uncommon complication post-solid-organ transplant (SOT), except among pediatric transplant patients and those seronegative for VZV. As the majority of SOT recipients are seropositive for VZV, herpes zoster (HZ) occurs frequently following SOT, particularly among recipients who are older (≥65 years of age) and those receiving more intensive immunosuppression. Transplant providers should aware of the increased risk for HZ-related complications such as dissemination, organ-specific involvement, and post-herpetic neuralgia. Treatment for localized zoster is primarily given as oral regimens, but those with more complicated presentations or those at risk for dissemination should be treated initially with IV therapy. Available antiviral prophylaxis regimens and vaccination strategies for varicella and HZ among these immunosuppressed patients remain a mainstay for prevention in the pre-and post-transplant periods. Finally, we discuss important approaches to addressing post-exposure prophylaxis and infection control practices for those SOT patients with documented VZV infections.

Influenza is responsible for significant morbidity after transplantation. We evaluated T-helper 1/T-helper 2 (Th2) cytokines and interleukin (IL) 10 levels during influenza infection in the posttransplant setting. Serum samples from 277 transplant recipients were analyzed at influenza diagnosis and 28 days later for interferon gamma (IFN-γ), IL-4, IL-13, and IL-10. IL-13 levels were associated with protection against pneumonia and intensive care unit (ICU) admission, whereas the IFN-γ/IL-13 ratio and IL-10 levels were associated with an increased risk of pneumonia and ICU admission. This association was independent of viral load. A skewing of immune responses toward Th2 in transplant patients appears to confer protection from severe influenza infection, independent of viral load., This work was supported through an investigator-initiated grant from Roche. A. G. L. and C. H. were funded with advanced postdoctoral mobility grants from the Swiss National Science Foundation (grant numbers P300PB_171603 and P2BEP3_175265, respectively).

The opioid epidemic has resulted in increasing the incidence of hepatitis C virus in the general population and more deceased organ donors with hepatitis C in the United States. We aim to describe how the changing donor landscape affects patterns of liver and kidney transplantation among donors, waitlist candidates, and transplanted recipients.Using data supplied by the United Network for Organ Sharing, we examined donor hepatitis C virus antibody (Ab) and nucleic acid testing (NAT) status, center waitlist patterns, and liver and kidney transplants and discards between 2015 and 2017 by 6-month periods.We observed an increase in donors with any marker of the hepatitis C virus (n = 283 [6.2%] in period 1 to n = 384 [7.4%] in period 5, P = .008) and antibody positive nucleic acid testing negative donors (n = 81 [1.8%] in period 1 to n = 131 [2.5%] in period 5, P.001). We observed a significant increase in aviremic recipients of liver transplants from antibody positive nucleic acid testing negative donors (n = 1 [1.7%] in period 1, to n = 27 [31.0%] in period 5, P = .005) and a significant decrease in the antibody positive nucleic acid testing positive liver discard rate (P = .01). By the end of the study, 75.8% (n = 97) of recipients of antibody positive nucleic acid testing negative kidneys were hepatitis C virus negative, an increase from 10.6% (n = 5) in period 1.The number of donors with the hepatitis C virus is increasing. We observed a concomitant increase in the transplantation of kidneys and livers from aviremic donors, and the recipient population of these organs is increasingly hepatitis C virus negative.

Purpose Outcomes of lung transplant recipients (LTR) hospitalized for COVID-19 and comparisons to non-lung solid organ transplant recipients (SOTR) are incompletely described. Methods Using a multicenter prospective registry of SOTR, we examined 28-day outcomes (mortality [primary outcome], intensive care unit (ICU) admission, mechanical ventilation, and bacterial pneumonia) among both LTR and non-lung SOTR hospitalized with laboratory-confirmed COVID-19 diagnosed between March 1, 2020 and September 21, 2020. Data were analyzed using Stata (StataCorp, College Station, TX); chi-square tests were used to compare categorical variables and multivariable logistic regression was used to assess risk factors for mortality. Results The cohort included 72 LTR and 392 non-lung SOTR (Table 1). Overall, 28-day mortality trended higher in LTR vs. non-lung SOTR (27.8% vs. 19.9%, P=0.136). Other 28-day outcomes were similar between LTR and non-lung SOTR: ICU admission (45.8% vs. 39.1%, P=0.28), mechanical ventilation (32.9% vs. 31.1%, P=0.78), and bacterial pneumonia (15.3% vs. 8.2%, P=0.063). Congestive heart failure, diabetes, age >65 years, and obesity (BMI >= 30) were independently associated with mortality in non-lung SOTR, but not in LTR (Table 2). Conclusion In this large prospective cohort comparing lung and non-lung SOTR hospitalized for COVID-19, there were high but not significantly different rates of short-term morbidity and mortality. Baseline comorbidities appeared to drive mortality in non-lung SOTR but not LTR. Further studies are needed to identify risk factors for mortality among LTR.

In Reply The observed rate of breakthrough disease (2%) during prophylaxis in our study1 is consistent with the rate in other clinical studies (1%-4%).2,3 Both CMV disease cases in the prophylaxis group were receiving intermittent hemodialysis and kidney-adjusted parenteral ganciclovir per manufacturer’s instructions. Inadequate dosing is unlikely given data showing that in solid organ transplant recipients with advanced kidney dysfunction, manufacturer’s recommended dosing results in relative drug overexposure, not underexposure.4 Excluding these 2 cases, the odds of CMV disease by 12 months (0.46 [95% CI, 0.191-1.05]; P = .08) and delayed-onset CMV disease (0.30 [95% CI, 0.11-0.82]; P = .01) still favored preemptive therapy vs prophylaxis.

Purpose Real-time polymerase chain reaction (RT-PCR) detection of severe acute respiratory syndrome coronavirus (SARS-CoV-2) is required for diagnosis of coronavirus disease 2019 (COVID-19). Sensitivity of RT-PCR nasopharyngeal (NP) testing is presumed to be high, but there is no gold standard against which this has been determined. The objective was to determine whether lower respiratory tract infection (LRTI), detected in bronchoalveolar lavage fluid (BALF), occurs in the absence of upper respiratory tract infection with clinical testing of both specimen types. Methods Between March 26, 2020 and April 17, 2020 at the University of Washington Medical Center all patients with BALF specimens clinically tested for SARS-CoV-2 were identified. We assessed the proportion of patients with positive RT-PCR for SARS-CoV-2 in BALF after negative NP testing. We describe 3 cases with positive testing in BALF. Results Among 16 patients with BALF samples, 3 cases (19%) had SARS-CoV-2 detected in BALF. In Case 1, negative NP testing occurred early in the infection and respiratory symptoms may have been missed due to neurologic injury. In Case 2, outpatient diagnosis was aspiration pneumonia, but clinical suspicion remained high for COVID-19 at hospitalization based on epidemiological and clinical features. All 3 cases involved older adults (age >65 years), one of whom was immunosuppressed in the setting of lung transplantation (Case 3). Conclusions These data demonstrate that SARS-CoV-2 LRTI occurs in the presence of negative NP testing. NP testing may underestimate the prevalence of COVID-19 and has implications for spread of SARS-CoV2 in the community and healthcare setting., Highlights • Negative nasopharyngeal testing may underestimate the true prevalence of COVID-19. • COVID-19 lower respiratory tract infection occurs despite negative NP testing. • False negative nasopharyngeal testing has implications for the spread of COVID-19.

The opioid epidemic has resulted in a potential increase in donors in the testing window period for hepatitis C virus (HCV). We analyzed HCV reports to the Disease Transmission Advisory Committee (DTAC) between 2008 and 2016 to estimate the risk of HCV transmission. In 15 of 95 (16%) reports, at least one recipient developed proven/probable donor-derived HCV resulting in 32 infected recipients. Seven transmissions occurred during the nucleic acid testing (NAT) window period; four occurred during serological window period. The other four transmission occurred due to human error (3) and false-negative serology (1). All seronegative-exposed liver and lung recipients contracted HCV; 18/21 (86%) kidney and 3/4 (75%) heart recipients developed HCV. Four transmitting donors died of intravenous drug overdose, three in 2016 and one in 2012. Among donors with a history of intravenous drug use (IVDU), drug intoxication as a mechanism of death, or increased risk status, and negative screening HCV testing, the risk of transmission to a recipient was about 1 in 1000. The overall risk of transmitting HCV from NAT-negative donors with IVDU is low and consistent with modeling data. This information may be helpful to clinicians counseling potential recipients offered these organs.

Background Adenovirus infection is associated with graft dysfunction and graft loss in pediatric cardiac, lung, and liver transplants in prior retrospective studies, but data in pediatric kidney transplant recipients is limited. Methods We conducted a prospective single-center cohort study of 75 consecutive pediatric kidney transplant recipients who underwent monthly screening for adenovirus viremia and symptom assessment for 2 years posttransplant. Results Adenovirus viremia was detected in 11 (14.7%) patients at a median onset of 173 days (interquartile range, 109-310 days) posttransplant, 6 (8%) had asymptomatic viremia, and 5 (6.7%) had symptomatic disease (2 with hematuria and 3 with an acute febrile respiratory illness). Viremic patients did not differ from nonviremic patients in age, immunosuppression management, or cytomegalovirus or Epstein-Barr virus serostatus, but were more likely to develop cytomegalovirus viremia during the first 2 years posttransplant. No patient had an increase in creatinine from baseline during the time of adenovirus viremia. In a Cox proportional hazards regression, subclinical adenovirus viremia was not associated with a faster time to a 30% decline in estimated glomerular filtration rate. Conclusions Adenovirus infection is common among pediatric kidney transplant recipients and frequently causes symptomatic disease; however, symptoms are often mild and are not associated with a decline in graft function. Routine monitoring for adenovirus viremia in pediatric kidney transplant recipients may not be warranted.

Background Seasonal influenza infection may cause significant morbidity and mortality in transplant recipients. The purpose of this study was to assess the epidemiology of symptomatic influenza infection posttransplant and determine risk factors for severe disease. Methods Twenty centers in the United States, Canada, and Spain prospectively enrolled solid organ transplant (SOT) or hematopoietic stem cell transplant (HSCT) recipients with microbiologically confirmed influenza over 5 consecutive years (2010-2015). Demographics, microbiology data, and outcomes were collected. Serial nasopharyngeal swabs were collected at diagnosis and upto 28 days, and quantitative polymerase chain reaction for influenza A was performed. Results We enrolled 616 patients with confirmed influenza (477 SOT; 139 HSCT). Pneumonia at presentation was in 134 of 606 (22.1%) patients. Antiviral therapy was given to 94.1% for a median of 5 days (range, 1-42 days); 66.5% patients were hospitalized and 11.0% required intensive care unit (ICU) care. The receipt of vaccine in the same influenza season was associated with a decrease in disease severity as determined by the presence of pneumonia (odds ratio [OR], 0.34 [95% confidence interval {CI}, .21-.55], P < .001) and ICU admission (OR, 0.49 [95% CI, .26-.90], P = .023). Similarly, early antiviral treatment (within 48 hours) was associated with improved outcomes. In patients with influenza A, pneumonia, ICU admission, and not being immunized were also associated with higher viral loads at presentation (P = .018, P = .008, and P = .024, respectively). Conclusions Annual influenza vaccination and early antiviral therapy are associated with a significant reduction in influenza-associated morbidity, and should be emphasized as strategies to improve outcomes of transplant recipients.

Background BK polyoma virus (BKPyV) has been associated with hemorrhagic cystitis (HC) after hematopoietic cell transplant (HCT). Prior studies have examined risk factors for BKPyV-associated HC, but have been limited by inclusion of pre-engraftment hemorrhagic cystitis or cases without macroscopic hemorrhage. Few studies have examined factors associated with the clinical course of BKPyV-HC. Methods We retrospectively analyzed allogeneic HCT recipients transplanted between 2007-2017, and included all patients with BKPyV-HC (defined as macroscopic hematuria [Bedi grade >/=2] and positive urine BKPyV PCR who had at least one available plasma BKPyV viral load sample after platelet engraftment or day 28 post-HCT. Duration was determined by time to resolution of hematuria and symptoms. Demographic, transplant, viral, and immune characteristics were investigated in multivariable models using time-varying covariates to determine factors associated with resolution of macroscopic hematuria, resolution of overall symptoms, need for continuous bladder irrigation (CBI) or surgical intervention, need for transfusion, or development of clots by day 90 after diagnosis. Results BKPyV-HC developed in 128 allogeneic HCT recipients (70% myeloablative conditioning) at a median of 58 days post-transplant (IQR 46 – 78) and the median time to symptom resolution was 23.5 days (15 - 44). Mortality by day 90 post-BKPyV-HC diagnosis was 20% [26/128]. Plasma viral load >/=10,000 at presentation was associated with both longer duration of macroscopic hematuria and longer duration of overall symptoms [aHRs for resolution 0.31 (95% CI 0.11, 0.91), 0.32 (95% CI 0.11, 0.95), respectively], but not associated with need for continuous bladder irrigation or surgical intervention [HR 1.15 (95% CI 0.42, 3.14)], development of clots [HR 1.31 (95% CI 0.50, 3.46)], or need for transfusion during their course [HR 1.62 (95% CI 0.44, 5.99)]. Absolute lymphocyte count Conclusion Both immune and viral characteristics were associated with a longer duration of BKPyV-associated HC. BKPyV-associated HC is a morbid disease in need of improved management strategies; accurate descriptions of disease severity and factors associated with prolonged recovery will inform end points of future clinical trials.

BACKGROUND Few studies have directly compared preemptive therapy (PET) and antiviral prophylaxis (AP) for prevention of cytomegalovirus (CMV) disease in CMV seropositive (R+) orthotopic liver transplant (OLT) recipients. METHODS We prospectively assessed CMV disease and clinical outcomes among 160 consecutive R+ OLT recipients who received PET (weekly plasma CMV PCR for 3 months, oral valganciclovir 900 mg twice daily for CMV viremia >250 IU/mL, until 2 consecutive negative weekly PCR results) and compared them with a historical cohort of 156 R+ recipients who received AP (valganciclovir, 900 mg daily for 3 months). RESULTS Patient characteristics were similar between PET and AP cohorts (P > 0.05 all comparisons). In the PET group, 24% (39/160) developed CMV viremia greater than 250 IU/mL at a median of 42 (range, 7-93) days post-OLT. CMV monitoring adherence in the PET cohort was 85% (1488/1760 required tests) and 86% (30/36) initiated PET within 3 days of the CMV result. By 12 months post-OLT, the incidence of CMV disease, acute allograft rejection, major infection, or death in the PET and AP cohorts was not significantly different: 2% versus 2%, 19% versus 16%, 10.5% versus 10.8%, and 5% versus 8%, respectively (P > 0.05 all comparisons). The estimated proportion of drug-exposed patients and average antiviral drug exposure were significantly lower with PET versus AP: 24% versus 100%, P < 0.001, and 15.8 versus 81 g per patient, P < 0.001, respectively. CONCLUSIONS PET is feasible in a nonresearch setting and is associated with similar CMV disease rates and other clinically relevant outcomes to AP in CMV seropositive liver transplant recipients.

Invasive fungal infections (IFIs) are a common complication in liver transplant recipients. There are no previous randomized trials of an echinocandin for the prevention of IFIs in solid organ transplant recipients. In a randomized, double-blind trial conducted at University-affiliated transplant centers, 200 high-risk liver transplant recipients (100 patients per group) received either anidulafungin or fluconazole for antifungal prophylaxis. Randomization was stratified by Model for End-Stage Liver Disease score ≥30 and receipt of a pretransplant antifungal agent. The primary end point was IFI in a modified intent-to-treat analysis. The overall incidence of IFI was similar for the anidulafungin (5.1%) and the fluconazole groups (8.0%) (OR 0.61, 95% CI 0.19-1.94, p = 0.40). However, anidulafungin prophylaxis was associated with less Aspergillus colonization or infection (3% vs. 9%, p = 0.08), lower breakthrough IFIs among patients who had received pretransplant fluconazole (0% vs. 27%, p = 0.07), and fewer cases of antifungal resistance (no cases vs. 5 cases). Both drugs were well-tolerated. Graft rejection, fungal-free survival, and mortality were similar for both groups. Thus, anidulafungin and fluconazole have similar efficacy for antifungal prophylaxis in most liver transplant recipients. Anidulafungin may be beneficial if the patient has an increased risk for Aspergillus infection or received fluconazole before transplantation.

The role of cytomegalovirus (CMV) reactivation in mediating adverse clinical outcomes in nonimmunosuppressed adults with critical illness is unknown.To determine whether ganciclovir prophylaxis reduces plasma interleukin 6 (IL-6) levels in CMV-seropositive adults who are critically ill.Double-blind, placebo-controlled, randomized clinical trial (conducted March 10, 2011-April 29, 2016) with a follow-up of 180 days (November 10, 2016) that included 160 CMV-seropositive adults with either sepsis or trauma and respiratory failure at 14 university intensive care units (ICUs) across the United States.Patients were randomized (1:1) to receive either intravenous ganciclovir (5 mg/kg twice daily for 5 days), followed by either intravenous ganciclovir or oral valganciclovir once daily until hospital discharge (n = 84) or to receive matching placebo (n = 76).The primary outcome was change in IL-6 level from day 1 to 14. Secondary outcomes were incidence of CMV reactivation in plasma, mechanical ventilation days, incidence of secondary bacteremia or fungemia, ICU length of stay, mortality, and ventilator-free days (VFDs) at 28 days.Among 160 randomized patients (mean age, 57 years; women, 43%), 156 patients received 1or more dose(s) of study medication, and 132 patients (85%) completed the study. The mean change in plasma IL-6 levels between groups was -0.79 log10 units (-2.06 to 0.48) in the ganciclovir group and -0.79 log10 units (-2.14 to 0.56) in the placebo group (point estimate of difference, 0 [95% CI, -0.3 to 0.3]; P .99). Among secondary outcomes, CMV reactivation in plasma was significantly lower in the ganciclovir group (12% [10 of 84 patients] vs 39% [28 of 72 patients]); absolute risk difference, -27 (95% CI, -40 to -14), P .001. The ganciclovir group had more median VFDs in both the intention-to-treat (ITT) group and in the prespecified sepsis subgroup (ITT group: 23 days in ganciclovir group vs 20 days in the placebo group, P = .05; sepsis subgroup, 23 days in the ganciclovir group vs 20 days in the placebo group, P = .03). There were no significant differences between the ganciclovir and placebo groups in duration of mechanical ventilation (5 days for the ganciclovir group vs 6 days for the placebo group, P = .16), incidence of secondary bacteremia or fungemia (15% for the ganciclovir group vs 15% for the placebo group, P = .67), ICU length of stay (8 days for the ganciclovir group vs 8 days for the placebo group, P = .76), or mortality (12% for the ganciclovir group vs 15% for the placebo group, P = .54).Among CMV-seropositive adults with critical illness due to sepsis or trauma, ganciclovir did not reduce IL-6 levels and the current study does not support routine clinical use of ganciclovir as a prophylactic agent in patients with sepsis. Additional research is necessary to determine the clinical efficacy and safety of CMV suppression in this setting.clinicaltrials.gov Identifier: NCT01335932.

Inflammation in the tumour microenvironment mediated by interleukin 1β is hypothesised to have a major role in cancer invasiveness, progression, and metastases. We did an additional analysis in the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS), a randomised trial of the role of interleukin-1β inhibition in atherosclerosis, with the aim of establishing whether inhibition of a major product of the Nod-like receptor protein 3 (NLRP3) inflammasome with canakinumab might alter cancer incidence.We did a randomised, double-blind, placebo-controlled trial of canakinumab in 10 061 patients with atherosclerosis who had had a myocardial infarction, were free of previously diagnosed cancer, and had concentrations of high-sensitivity C-reactive protein (hsCRP) of 2 mg/L or greater. To assess dose-response effects, patients were randomly assigned by computer-generated codes to three canakinumab doses (50 mg, 150 mg, and 300 mg, subcutaneously every 3 months) or placebo. Participants were followed up for incident cancer diagnoses, which were adjudicated by an oncology endpoint committee masked to drug or dose allocation. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, NCT01327846. The trial is closed (the last patient visit was in June, 2017).Baseline concentrations of hsCRP (median 6·0 mg/L vs 4·2 mg/L; p0·0001) and interleukin 6 (3·2 vs 2·6 ng/L; p0·0001) were significantly higher among participants subsequently diagnosed with lung cancer than among those not diagnosed with cancer. During median follow-up of 3·7 years, compared with placebo, canakinumab was associated with dose-dependent reductions in concentrations of hsCRP of 26-41% and of interleukin 6 of 25-43% (p0·0001 for all comparisons). Total cancer mortality (n=196) was significantly lower in the pooled canakinumab group than in the placebo group (p=0·0007 for trend across groups), but was significantly lower than placebo only in the 300 mg group individually (hazard ratio [HR] 0·49 [95% CI 0·31-0·75]; p=0·0009). Incident lung cancer (n=129) was significantly less frequent in the 150 mg (HR 0·61 [95% CI 0·39-0·97]; p=0·034) and 300 mg groups (HR 0·33 [95% CI 0·18-0·59]; p0·0001; p0·0001 for trend across groups). Lung cancer mortality was significantly less common in the canakinumab 300 mg group than in the placebo group (HR 0·23 [95% CI 0·10-0·54]; p=0·0002) and in the pooled canakinumab population than in the placebo group (p=0·0002 for trend across groups). Fatal infections or sepsis were significantly more common in the canakinumab groups than in the placebo group. All-cause mortality did not differ significantly between the canakinumab and placebo groups (HR 0·94 [95% CI 0·83-1·06]; p=0·31).Our hypothesis-generating data suggest the possibility that anti-inflammatory therapy with canakinumab targeting the interleukin-1β innate immunity pathway could significantly reduce incident lung cancer and lung cancer mortality. Replication of these data in formal settings of cancer screening and treatment is required.Novartis Pharmaceuticals.

The new kidney allocation system (KAS) intends to allocate the top 20% of kidneys to younger recipients with longer life expectancy. We hypothesized that the new KAS would lead to greater allocation of Public Health Service (PHS) increased-risk donor organs to younger recipients.Analyses of the Organ Procurement and Transplantation Network data of patients who underwent primary deceased kidney transplantation were performed in pre- and post-KAS periods.The allocation of PHS increased-risk kidney allografts in various age groups changed significantly after implementation of the new KAS, with an increased proportion of younger individuals receiving increased-risk kidneys (7% vs 10% in age group 20-29 y and 13% vs 18% in age group 30-39 y before and after KAS, respectively; P .0001). This trend was reversed in recipients 50-59 years old, with 31% in the pre-KAS period compared with 26% after KAS (P .0001).The new KAS resulted in a substantial increase in allocation of PHS increased-risk kidneys to candidates in younger age groups. Because increased-risk kidneys are generally underutilized, future efforts to optimize the utilization of these organs should target younger recipients and their providers.

Background Ganciclovir-resistant (ganR) cytomegalovirus (CMV) is an emerging and important problem in solid organ transplant (SOT) recipients. Only through direct comparison of ganR- and ganciclovir-sensitive (ganS) CMV infection can risk factors and outcomes attributable specifically to ganciclovir resistance appropriately be determined. Methods We performed a retrospective, case-control (1:3) study of SOT recipients with genotypically confirmed ganR-CMV (n = 37) and ganS-CMV infection (n = 109), matched by donor/recipient CMV serostatus, year and organ transplanted, and clinical manifestation. We used χ2 (categorical) and Mann-Whitney (continuous) tests to determine predisposing factors and morbidity attributable to resistance, and Kaplan-Meier plots to analyze survival differences. Results The rate of ganR-CMV was 1% (37/3467) overall and 4.1% (32/777) among CMV donor-positive, recipient-negative patients, and was stable over the study period. GanR-CMV was associated with increased prior exposure to ganciclovir (median, 153 vs 91 days, P < .001). Eighteen percent (3/17) of lung transplant recipients with ganR-CMV had received

SUMMARYOne case of hospital-acquired listeriosis was linked to milkshakes produced in a commercial-grade shake freezer machine. This machine was found to be contaminated with a strain ofListeria monocytogenesepidemiologically and molecularly linked to a contaminated pasteurized, dairy-based ice cream product at the same hospital a year earlier, despite repeated cleaning and sanitizing. Healthcare facilities should be aware of the potential for prolongedListeriacontamination of food service equipment. In addition, healthcare providers should consider counselling persons who have an increased risk forListeriainfections regarding foods that have causedListeriainfections. The prevalence of persistentListeriacontamination of commercial-grade milkshake machines in healthcare facilities and the risk associated with serving dairy-based ice cream products to hospitalized patients at increased risk for invasiveL. monocytogenesinfections should be further evaluated.

Background CMV disease is a major cause of morbidity and mortality in OHTR, especially among D+R− patients. Clinical trials of longer antiviral prophylaxis have shown reduced CMV disease incidence in kidney and lung transplant recipients but have not been done in OHTR. We aimed to characterize risk factors and impact of antiviral prophylaxis duration on CMV disease in high-risk CMV D+R− OHTR. Methods We performed a retrospective cohort study of consecutive adult first OHTR at a single US transplant center from 5 July 2005 through 30 December 2016 with at least one year of follow-up. Standard immunosuppression included ATG induction followed by maintenance with tacrolimus, mycophenolate, and prednisone. Valganciclovir (VGCV) was given for 3 months for all R+ and for 3–6 months for D+R− at clinician discretion. CMV syndrome and end-organ disease were defined using consensus definitions. Chi square and Mann–Whitney tests were used to compare categorical and continuous variables, respectively, with P < 0.05 considered significant, and logistic regression was used for multivariate analysis. Results Key cohort (n = 310) characteristics included: 73% male, median age 55, 98% ATG induction, 1-year survival of 92%, and median follow-up of 44 months (IQR 22–88). Proven/probable CMV disease occurred in 27/310 (9%: syndrome 22%, end-organ 78%), and more frequently in D+R− (22/83, 27%) vs. either R+: 5/180 (2.8%) or D−R−: 0/47, P < 0.01. Among D+R− recipients who survived to hospital discharge, CMV disease occurred >1 year post-OHT in 10/22 (45%), and was genotypicallyconfirmed as ganciclovir-resistant in 4/22 (18%). Duration of VGCV prophylaxis ranged from 0 to 8.9 months (median 3.6, IQR 3.3–5.6). In a multivariable model that assessed baseline and time-dependent factors, longer durations of prophylaxis (analyzed continuously or discretely) were not associated with protection against CMV disease (P > 0.05 for all comparisons). Conclusion CMV disease remains a major clinical problem in D+R− OHTR, and longer durations of antiviral prophylaxis do not appear to be protective. Prophylaxis duration should be studied specifically in OHTR, rather than extrapolated from other organ transplant populations. Novel strategies to prevent CMV disease in D+R− OHTR are warranted. Disclosures A. Limaye, Merk: Consultant and Investigator, Consulting fee and Research grant; Astellas Pharma Inc.: Consultant and Investigator, Consulting fee; Helocyte Inc.: Consultant, Consulting fee.

Background BK polyoma virus (BKPyV) has been associated with hemorrhagic cystitis after HCT. Prior studies have examined risk factors for BKPyV-associated HC, but the characteristics of disease, including duration, common presentations, and the spectrum of clinical outcomes, have not been well described. Precise estimates of major clinical endpoints are critical to design clinical trials of novel prevention and treatment agents. Methods We retrospectively analyzed HCT patients between 2007 and 2017. Subjects were included if they had macroscopic hematuria (Bedi grade ≥2), a positive urine BKPyV PCR, and at least one plasma BKPyV viral load available after platelet engraftment or Day 28 post-HCT. HC was defined by hematuria and positive urine BKPyV PCR; duration was determined by time to resolution of hematuria. Demographic data, baseline symptoms, and clinical outcomes (e.g., need for bladder irrigation, use of cidofovir) were reviewed. Results BKPyV-HC developed in 149 HCT recipients (97.3% allogeneic, 73% myeloablative conditioning) at a median of 54 days post-transplant (IQR 40–73). Seven percent were co-infected with adenovirus at the time of diagnosis. Symptoms and outcomes are shown in Table 1. Of those with plasma viral load testing at the onset of HC, 91% (112/126) had BKPyV viremia with a median viral load of 2,200 copies/mL (IQR 385–9,300). Twenty-nine percent of the cohort received cidofovir. Conclusion We describe the characteristics of BKPyV-associated HC in HCT recipients in the modern era of immunosuppression. BKPyV-associated HC is a morbid disease in need of improved management strategies; patient-centered estimates of outcomes are crucial for evaluating new agents. Table 1. Symptoms and outcomes of BKPyV-associated HC BKPyV- HC n = 149 (%) Clots in urine* 92 (60) Dysuria* 124 (81) Frequency* 91 (59) Urgency* 68 (44) Flank pain* 22 (14) Abdominal pain* 30 (20) Median duration of symptoms in days (IQR) 25 (14–49) Median duration of hematuria or urine clots in days (IQR) 18 (12–39) Median duration of phenazopyridine or oxybutynin use in days (IQR) 19 (8–34.5) Need for pain medication† 109 (71) Need for Foley placement† 49 (32) Need for continuous bladder irrigation† 26 (17) Need for surgical intervention† 9 (6) *At presentation. †Any time during course. Disclosures S. Pergam, Merck: Consultant, Consulting fee; Chimerix: Consultant, Consulting fee. A. Limaye, Novartis: Consultant, Consulting fee. M. Boeckh, Vir Biotechnology: Consultant and Grant Investigator, Consulting fee and Research grant; Chimerix Inc: Consultant, Grant Investigator and Investigator, Consulting fee, Research grant and Research support.

Background CMV reactivation in seropositive, non-immunosuppressed adults with sepsis has been associated with worse clinical outcomes. To inform rational design of interventional trials determining whether CMV prevention improves outcomes, it is critical to identify the independence and strength of the association of CMV reactivation measures with clinically-relevant endpoints. Identification of patient factors associated with CMV reactivation would allow for optimization of the study population. Methods We performed a secondary pooled analysis of two prospective cohorts with sepsis: an observational cohort of ICU patients (n = 40) and the placebo cohort from a randomized, double-blind trial of ganciclovir to prevent CMV reactivation in acute critical illness (n = 66). Personnel blinded to the PCR results assessed clinical variables; CMV DNAemia was measured by quantitative plasma PCR twice weekly. Multivariable modeling using logistic and linear methods was used to examine the associations of CMV with clinical outcomes and between baseline patient factors and measures of CMV reactivation (adjusted for age, race, gender, transfusion status, study cohort, and APACHE score). Results CMV reactivation occurred at any level in 38/106 (36%), at >100 IU/mL in 25/106 (24%), and at >1,000 IU/mL in 14/106 (13%). In a multivariate model, CMV reactivation at any level, >100 IU/mL, or >1,000 IU/mL was associated with fewer days alive and not requiring ventilation: mean difference of −3.5 days ([95% CI −7.0, 0], P = 0.057), −5.1 days ([−8.9, −1.2], P = 0.012), and −6.1 days ([−10.9, −1.2], P = 0.016), respectively. Multiple measures of CMV reactivation were associated with other clinically-relevant outcomes, even after adjustment for baseline factors (Table 1). The association of APACHE score with CMV reactivation measures was inconsistent and with small effect size. We did not identify other patient variables associated with subsequent CMV reactivation. Conclusion CMV reactivation in seropositive adults with sepsis is independently and quantitatively associated with clinically-important outcomes, including death or continued hospitalization by day 28, ventilator-, ICU-, and hospital-free days. These effect sizes provide key data to inform design parameters of future interventional trials. Disclosures All authors: No reported disclosures.

The ability to identify bacterial pathogens at the subspecies level in clinical diagnostics is currently limited. We investigated whether splitting Escherichia coli species into clonal groups (clonotypes) predicts antimicrobial susceptibility or clinical outcome. A total of 1,679 extraintestinal E. coli isolates (collected from 2010 to 2012) were collected from one German and 5 U.S. clinical microbiology laboratories. Clonotype identity was determined by fumC and fimH (CH) sequencing. The associations of clonotype with antimicrobial susceptibility and clinical variables were evaluated. CH typing divided the isolates into >200 CH clonotypes, with 93% of the isolates belonging to clonotypes with ≥2 isolates. Antimicrobial susceptibility varied substantially among clonotypes but was consistent across different locations. Clonotype-guided antimicrobial selection significantly reduced “drug-bug” mismatch compared to that which occurs with the use of conventional empirical therapy. With trimethoprim-sulfamethoxazole and fluoroquinolones, the drug-bug mismatch was predicted to decrease 62% and 78%, respectively. Recurrent or persistent urinary tract infection and clinical sepsis were significantly correlated with specific clonotypes, especially with CH40-30 (also known as H30), a recently described clonotype within sequence type 131 (ST131). We were able to clonotype directly from patient urine samples within 1 to 3 h of obtaining the specimen. In E. coli , subspecies-level identification by clonotyping can be used to significantly improve empirical predictions of antimicrobial susceptibility and clinical outcomes in a timely manner.

Parainfluenza virus (PIV) may cause life‐threatening pneumonia in lung transplant patients and there are no proven effective therapies. We report the use of inhaled DAS181, a novel sialidase fusion protein, to treat severe PIV type 3 pneumonia in a lung transplant patient. Treatment was well tolerated and associated with improvement in oxygenation and symptoms, along with rapid clearance of PIV. DAS181 should be systematically evaluated for treatment of PIV infection in transplant recipients.

With the need for organs far exceeding supply, donors previously exposed to hepatitis B (HBV) and hepatitis C (HCV) viral infections should be considered for transplantation. Although many centers have protocols for transplanting organs from HBV core antibody-positive (HBcAb+) donors into select recipients, in the era of direct-acting antivirals (DAAs), a new focus should be placed on HCV-positive donors. The transmission rate from HCV antibody-positive (HCVAb+) nucleic acid testing negative (HCV NAT-) donors is expected to be very low, and we encourage use of such organs in HCV recipients provided a normal biopsy, appropriate counseling, and careful post-transplant monitoring. While transmission of HCV from HCV NAT+ donors is universal, the success of DAA in obtaining a sustained viral response in post-transplant recipients should make the use of these organs more appealing. We herein provide information to help guide the use of organs from HCV donors.