Increasing Proportion of High-risk Cytomegalovirus Donor-positive/Recipient-negative Serostatus in Solid Organ Transplant Recipients.

BACKGROUND: Cytomegalovirus (CMV) donor-positive/recipient-negative (D+R-) serostatus is independently associated with worse allograft and patient survival across solid organ transplant (SOT) types. We characterized trends in CMV D+R- serostatus among adult SOT recipients performed in the United States. METHODS: Donor (D) and recipient (R) CMV serostatus and demographic factors were obtained from the Scientific Registry of Transplant Recipients for persons ≥18 y undergoing a first SOT between January 1, 2000, and December 31, 2020. The proportions of D+R- SOTs over time were assessed using Chi square for trend and modeled through 2040. Factors associated with D/R seropositivity were assessed using logistic models. RESULTS: Among 472 549 SOTs, the average proportion of D+R- SOTs increased significantly among kidney, liver, heart, and lung between 2000 to 2009 and 2010 to 2020: 18.0% to 18.3% ( P = 0.034), 19.4% to 21.8% ( P < 0.001), 22.2% to 25.5% ( P < 0.001), and 23.6% to 27.0% ( P < 0.001), respectively. The increased proportion over time resulted from a disproportionate increase in R- (34.9% to 37.0% for all organ types, P < 0.001) and a smaller corresponding change in D+ (60.8% to 60.3%, P < 0.001). CONCLUSIONS: The proportion of high-risk CMV D+R- SOTs increased significantly across all organs and is projected to continue to increase. These findings inform population-level strategies to mitigate the negative impact of CMV D+R- in SOT.

Unexpected Cytomegalovirus (CMV) Replication Kinetics in CMV Donor-Seropositive, Recipient-Seronegative Liver Transplant Recipients Receiving Preemptive Antiviral Therapy.

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.

Cytomegalovirus Serostatus and Functional Impairment in Liver Transplant Recipients in the Current Era.

BACKGROUND: Whether donor (D+) or recipient (R+) cytomegalovirus (CMV) seropositivity is associated with functional impairment in liver transplant recipients is not known. METHODS: Patients included adult liver transplant recipients in the Organ Procurement and Transplantation Network database transplanted over a five-year period from 1 January 2014-31 December 2018. Functional status in the database was assessed using Karnofsky performance scale. A logistic regression model that controlled for potential confounders was used to examine the association of CMV serostatus and functional status. Variables significantly associated with functional status (p < 0.05) were then used to develop propensity score and propensity score matched analysis was conducted where each patient was compared with a matched-control with the same propensity score. RESULTS: Among 30,267 adult liver transplant recipients, D+ or R+ patients had significantly lower functional status at last follow-up than the D-R- cohort (OR 0.88, 95% CI 0.80-0.96, p = 0.007). In propensity score matched model, D+ or R+ patients had significantly lower functional status than matched-controls (p = 0.009). D+ or R+ CMV serostatus (p = 0.018) and low functional level (p < 0.001) were also independently associated with infections as cause-of-death. CONCLUSIONS: D+ or R+ liver transplant recipients had lower functional status and higher risk of deaths due to infections. Future studies are warranted to examine the mechanistic basis of these findings in the setting of transplantation.

Outpatient Fluoroquinolone Prescription Fills in the United States, 2014 to 2020: Assessing the Impact of Food and Drug Administration Safety Warnings.

The impact of United States Food and Drug Administration (FDA) safety warnings on outpatient fluoroquinolone use is unclear. Annual changes in outpatient ciprofloxacin, levofloxacin, and moxifloxacin prescription fills (IQVIA National Prescription Audit databases) were assessed using a regression model. Monthly fills during baseline (August 2014 to April 2016) and first (May 2016 to June 2018) and second FDA warning periods (July 2018 to February 2020) were compared by interrupted time series analysis. From 2015 through 2019, total fluoroquinolone fills decreased from 35,616,786 (111.1/1,000 persons) to 21,100,050 (64.3/1,000 persons) annually (10.8% annually [P = 0.001]). Ciprofloxacin, levofloxacin, and moxifloxacin fills decreased annually by 10.4% (P = 0.001), 11.2% (P < 0.001), and 17.7% (P = 0.008), respectively. During the baseline period, there was no significant change in monthly fluoroquinolone fills. In May 2016 and during the first warning period, monthly fluoroquinolone fills decreased significantly (P < 0.001); the trend of decreased fills was significantly greater than that of the baseline period (P = 0.02). There was no change in fluoroquinolone fills in July 2018. Monthly fills decreased significantly throughout the second warning period (P < 0.001), but the trend did not differ from that of the first warning period. Trends for ciprofloxacin, the most commonly prescribed fluoroquinolone, were similar to those for the class. Fills of prescriptions by infectious diseases specialists (P < 0.005) and nurse practitioners (P = 0.04) significantly increased during the study. U.S. outpatient fluoroquinolone prescription fills significantly decreased from August 2014 to February 2020, most strongly in association with May 2016 FDA warnings. FDA safety warnings are useful tools for leveraging outpatient antimicrobial stewardship.

Association of HHV-6 With Outcomes in CMV-seronegative Liver Transplant Recipients With CMV-seropositive Donors Receiving Preemptive Antiviral Therapy.

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.

Risk Factors for Cytomegalovirus Viremia following Liver Transplantation With a Seropositive Donor and Seronegative Recipient Receiving Antiviral Therapy.

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.

Impact of Revised Infectious Diseases Society of America and Society for Healthcare Epidemiology of America Clinical Practice Guidelines on the Treatment of Clostridium difficile Infections in the United States.

BACKGROUND: Our objective was to determine if oral vancomycin, fidaxomicin, and oral metronidazole use in the United States changed after publication of revised clinical practice guidelines for Clostridium difficile infection (CDI) in February 2018. METHODS: We obtained US antibiotic prescription data (IQVIA) from 2006-August 2019 and used guideline-recommended dosing regimens to estimate monthly numbers of 10-day treatment courses of vancomycin, fidaxomicin and metronidazole. Interrupted time-series analyses were performed, adjusted by month. We compared linear trends for monthly numbers of treatment courses in different time periods. RESULTS: Cumulative treatment courses of oral vancomycin and fidaxomicin increased by 54% (n = 226 166) and 48% (n = 18 518), respectively, in 18 months following guidelines compared with 18 months before; those of oral metronidazole decreased by 3% (n = 238 372). Monthly vancomycin and fidaxomicin use significantly increased throughout the period following revised guidelines (P < .0001 and P = .0002, respectively), whereas that of metronidazole decreased significantly (P < .0001). Monthly vancomycin use increased and metronidazole use decreased to a significantly greater extent after publication of revised guidelines than after publication of clinical trials establishing superiority of vancomycin over metronidazole (P < .0001). CONCLUSIONS: Revised practice guidelines have had a significant impact on CDI treatment in the US. Clinical trial data used for the revised guidelines were available since 2007-2014 and 2011-2012 for oral vancomycin and fidaxomicin, respectively. Guidelines or guidance documents for treating CDI and other infections should be updated in more timely fashion.

Cost-effectiveness of Preemptive Therapy Versus Prophylaxis in a Randomized Clinical Trial for the Prevention of Cytomegalovirus Disease in Seronegative Liver Transplant Recipients With Seropositive Donors.

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.

Decreased Overall and Inappropriate Antibiotic Prescribing in a Veterans Affairs Hospital Emergency Department following a Peer Comparison-Based Stewardship Intervention.

Antibiotic prescribing is very common in emergency departments (EDs). Optimal stewardship intervention strategies in EDs are not well defined. We conducted a prospective, observational cohort study in a Veterans Affairs ED in which clinician education and monthly e-mail-based peer comparisons were directed against all oral antibiotic prescribing for discharged patients. Oral antibiotic prescriptions were compared in baseline (June 2016 to December 2017) and intervention (January to June 2018) periods using an interrupted time series regression model. Prescribing appropriateness was compared during January to June 2017 and the intervention period. During the intervention period, antibiotic prescriptions decreased monthly by 10.4 prescriptions per 1,000 ED visits (P = 0.07 [95% confidence interval {CI}, -21.7 to 1.0]). The relative decrease in the trend of antibiotic prescriptions during the intervention period compared to baseline was 9.9 prescriptions per 1,000 ED visits per month (P = 0.07 [95% CI, -20.9 to 1.0]). The intervention was associated with a significant decrease and increase in amoxicillin-clavulanate and cephalexin prescriptions, respectively (P < 0.001, P = 0.004). Decreasing trends in ciprofloxacin prescriptions during the baseline period were maintained during the intervention. Unnecessary antibiotic prescribing (i.e., antibiotic not indicated) decreased from 55.6% to 38.7% during the intervention (30.4% decrease, P = 0.003). Optimal antibiotic prescribing (i.e., antibiotics were indicated, and a guideline-concordant agent was prescribed for guideline-concordant duration) increased by 36% (21.6% to 29.3%, P = 0.12). A peer comparison-based stewardship intervention directed at ED clinicians was associated with reductions in overall and unnecessary oral antibiotic prescribing. There is potential to further improve antibiotic use as suboptimal prescribing remained common.

Antibiotic Consumption and Stewardship at a Hospital outside of an Early Coronavirus Disease 2019 Epicenter.

There are scant data on the impact of coronavirus disease 2019 (COVID-19) on hospital antibiotic consumption, and no data from outside epicenters. At our nonepicenter hospital, antibiotic days of therapy (DOT) and bed days of care (BDOC) were reduced by 151.5/month and 285/month, respectively, for March to June 2020 compared to 2018-2019 (P = 0.001 and P < 0.001). DOT per 1,000 BDOC was increased (8.1/month; P = 0.001). COVID-19 will impact antibiotic consumption, stewardship, and resistance in ways that will likely differ temporally and by region.

Effect of Preemptive Therapy vs Antiviral Prophylaxis on Cytomegalovirus Disease in Seronegative Liver Transplant Recipients With Seropositive Donors: A Randomized Clinical Trial.

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, <1% [95% CI, -4% to 4%]), and neutropenia (13% vs 10%; difference, 3% [95% CI, -5% to 12%]) did not differ significantly for the preemptive therapy vs antiviral prophylaxis group, respectively. All-cause mortality at last follow-up was 15% in the preemptive therapy vs 19% in the antiviral prophylaxis group (difference, 4% [95% CI, -14% to 6%]; P = .46). Conclusions and Relevance: Among CMV-seronegative liver transplant recipients with seropositive donors, the use of preemptive therapy, compared with antiviral prophylaxis, resulted in a lower incidence of CMV disease over 12 months. Further research is needed to replicate these findings and assess long-term outcomes. Trial Registration: ClinicalTrials.gov Identifier: NCT01552369.

Impact of the Coronavirus Disease 2019 Pandemic on Outpatient Antibiotic Prescriptions in the United States.

In April 2020, there were significant reductions in prescription fills of each of the 10 most prescribed outpatient antibiotics in the United States. Monthly azithromycin, amoxicillin-clavulanate, and levofloxacin fills did not rebound significantly from April through July 2020. Coronavirus disease 2019 had an immediate and sustained impact on US outpatient antibiotic prescribing.

Point-of-use filters for prevention of health care-acquired Legionnaires' disease: Field evaluation of a new filter product and literature review.

BACKGROUND: The Centers for Medicare & Medicaid Services requires that health care facilities assess their building water systems and minimize the risk of growth and spread of Legionella and other waterborne pathogens. Increasingly, point-of-use (POU) filters are being used to prevent exposure to these pathogens. This study provides efficacy and performance specifications (membrane size, pore size, and use restrictions), which will aid in selecting POU filters. METHODS: New faucet and shower filters rated for 62 days of use were evaluated at an acute care facility in Southwestern Ontario, Canada. Five faucets and 5 showers served as controls or were equipped with filters. Hot water samples were collected weekly for 12 weeks and cultured for Legionella, heterotrophic plate count, and Pseudomonas. Literature searches for articles on POU filters used in health care settings were performed using PubMed and Google Scholar. Filter specifications from 5 manufacturers were also compared. RESULTS: The 62-day POU filters installed on both faucets and showers eliminated Legionella and reduced heterotrophic plate count concentrations for 12 weeks. No Pseudomonas was recovered during this study. Twenty peer-reviewed studies are summarized, and 21 features of 53 POU filters have been compiled. CONCLUSIONS: The information provides infection preventionists and facility engineers with information to verify claims from manufacturers and compare differences among POU products, including validated efficacy, filter design, and operational specifications.

Sustained Reductions in Overall and Unnecessary Antibiotic Prescribing at Primary Care Clinics in a Veterans Affairs Healthcare System Following a Multifaceted Stewardship Intervention.

BACKGROUND: Most antibiotic prescribing is in outpatient settings. However, antibiotic stewardship has focused overwhelmingly on hospitalized patients. In a few studies, behavioral interventions decreased unnecessary outpatient prescribing against acute respiratory infections, but data are conflicting on sustained benefits after intervention discontinuation. METHODS: We conducted a prospective, observational study in 7 primary care clinics, in which an intervention comprised of clinician education, peer comparisons, and computer decision support order sets was directed against all antibiotic prescribing. After 6 months, peer comparisons were discontinued. Antibiotic prescribing was compared in the baseline (January-June 2016), intervention (January-June 2017), and postintervention (January-June 2018) periods. RESULTS: Mean antibiotic prescriptions significantly decreased from 76.9 (baseline) to 49.5 (intervention) and 56.3 (postintervention) per 1000 visits (35.6% and 26.8% reductions, respectively; P values < .001). The rate of unnecessary antibiotic prescribing (ie, antibiotic not indicated) decreased from 58.8% (baseline) to 37.8% (intervention) and 44.3% (postintervention) (35.7% and 24.7% decreases, respectively; P = .001 and P = .01). Overall, 19.9% (27/136), 36.6% (66/180), and 34.9% (67/192) of antibiotics were prescribed optimally (ie, antibiotics were indicated, and a guideline-concordant agent was prescribed for guideline-concordant duration) during the baseline, intervention, and postintervention periods, respectively (baseline vs intervention and postintervention, P = .001 and P = .003, respectively). Differences between intervention and postintervention periods in overall, unnecessary, or optimal antibiotic prescribing were not significant. CONCLUSIONS: A multifaceted outpatient stewardship intervention achieved reductions in overall, unnecessary, and suboptimal antibiotic prescription rates, which were sustained for a year after components of the intervention were discontinued. There is opportunity for further improvement, as inappropriate and suboptimal prescribing remained common.

Water Quality as a Predictor of Legionella Positivity of Building Water Systems.

Testing drinking water systems for the presence of Legionella colonization is a proactive approach to assess and reduce the risk of Legionnaires' disease. Previous studies suggest that there may be a link between Legionella positivity in the hot water return line or certain water quality parameters (temperature, free chlorine residual, etc.) with distal site Legionella positivity. It has been suggested that these measurements could be used as a surrogate for testing for Legionella in building water systems. We evaluated the relationship between hot water return line Legionella positivity and other water quality parameters and Legionella colonization in premise plumbing systems by testing 269 samples from domestic cold and hot water samples in 28 buildings. The hot water return line Legionella positivity and distal site positivity only demonstrated a 77.8% concordance rate. Hot water return line Legionella positivity compared to distal site positivity had a sensitivity of 55% and a specificity of 96%. There was poor correlation and a low positive predictive value between the hot water return line and distal outlet positivity. There was no correlation between Legionella distal site positivity and total bacteria (heterotrophic plate count), pH, free chlorine, calcium, magnesium, zinc, manganese, copper, temperature, total organic carbon, or incoming cold-water chlorine concentration. These findings suggest that hot water return line Legionella positivity and other water quality parameters are not predictive of distal site positivity and should not be used alone to determine the building's Legionella colonization rate and effectiveness of water management programs.

Improved Antibiotic Prescribing within a Veterans Affairs Primary Care System through a Multifaceted Intervention Centered on Peer Comparison of Overall Antibiotic Prescribing Rates.

Reducing inappropriate outpatient antibiotic use is an important national goal. Limited data exist on targeted education and peer comparison of overall antibiotic prescribing rates as an antimicrobial stewardship strategy. Primary care professionals (PCPs) from all seven clinics within our health care system were offered an education session, followed by monthly e-mails with their antibiotic prescribing rate, peer prescribing rates, and a system target. A pre-post analysis was conducted to compare prescribing rates during the intervention period (January to June 2017) to a seasonal baseline (January to June 2016) using a regression model. A random sample of prescriptions was reviewed for adherence to consensus guidelines. Educational sessions were attended by 68.5% (50/73) of PCPs. From the baseline to the intervention period, the mean rate of monthly antibiotic prescriptions declined from 76.9 to 49.5 per 1,000 office visits (35.6% reduction [P < 0.001]). Among reviewed cases, unnecessary antibiotic prescribing declined (58.8% [80/136] versus 38.9% [70/180]; 33.9% reduction [P = 0.0006]), and the rate of optimally prescribed antibiotics increased (19.9% [27/136] versus 30% [54/180]; 50.8% increase [P = 0.05]). If an antibiotic was indicated, there were no significant differences in prescribing of guideline-discordant agents (21.4% [12/56] versus 19.1% [21/110] [P = 0.8]) or guideline-concordant agents for a guideline-discordant duration (38.6% [17/44] versus 39.3% [35/89] [P = 1]). There were significant reductions in azithromycin and fluoroquinolone prescriptions (50.9% and 59.4% [P values of <0.001], respectively), but most prescriptions for these agents in the intervention period remained inappropriate. Initial education followed by monthly peer comparison of overall antibiotic prescribing rates reduced total and unnecessary antibiotic prescribing in primary care clinics.

Inflammasome expression and cytomegalovirus viremia in critically ill patients with sepsis.

BACKGROUND: CMV viremia is a contributor to poor outcomes in critically ill patients with sepsis. OBJECTIVES: To assess the expression levels of genes encoding inflammasome-related proteins in the development of CMV viremia in critically ill patients with sepsis. STUDY DESIGN: A cohort of CMV-seropositive critically ill patients with sepsis due to bloodstream infection underwent weekly testing for CMV viremia. Blood samples to evaluate mRNA levels of genes encoding CASP1, ASC, NLRP1, NLRP3, and NLRP12 were collected at the time of enrollment. Clinical outcomes were assessed at 30days or until death/discharge from ICU. RESULTS: CMV viremia was documented in 27.5% (8/29) of the patients, a median of 7days after the onset of bacteremia. Patients with sepsis who developed CMV viremia had higher CASP1 although this was not statistically significant (relative mean 3.6 vs 1.8, p=0.13). Development of high grade CMV viremia however, was significantly associated with CASP1; septic patients who developed high grade CMV viremia had significantly higher CASP1than all other patients (relative mean 5.5 vs 1.8, p=0.016). CONCLUSIONS: These data document possible involvement of inflammasome in the pathogenesis of CMV. Regulating the host immune response by agents that target these genes may have implications for improving CMV-related outcomes in these patients.

Unique characteristics of cryptococcosis identified after death in patients with liver cirrhosis: comparison with concurrent cohort diagnosed antemortem.

Characteristics of cirrhosis-associated cryptococcosis first diagnosed after death are not fully known. In a multicenter study, data generated as standard of care was systematically collected in 113 consecutive patients with cirrhosis and cryptococcosis followed for 80 patient-years. The diagnosis of cryptococcosis was first established after death in 15.9% (18/113) of the patients. Compared to cases diagnosed while alive, these patients had higher MELD score (33 vs. 22, P = .029) and higher rate of cryptococcemia (75.0% vs. 41.9%, P = .027). Cases diagnosed after death, in comparison to those diagnosed during life were more likely to present with shock (OR 3.42, 95% CI 1.18-9.90, P = .023), require mechanical ventilation at admission (OR 8.5, 95% CI 2.74-26.38, P = .001), less likely to undergo testing for serum cryptococcal antigen (OR 0.07, 95% CI 0.02-0.21, P < .001) and have positive antigen when the test was performed (OR 0.07, 95% CI 0.01-0.60, P = .016). In a subset of cirrhotic patients with advanced liver disease cryptococcosis was first recognized after death. These patients had the characteristics of presenting with fulminant fungemia, were less likely to have positive serum cryptococcal antigen and posed a diagnostic challenge for care providers.