bluuebunny/crossref_metadata_2025 huggingface dataset:
Targeting genomic SARS-CoV-2 RNA with siRNAs allows efficient inhibition of viral replication and spread
Authors: Ambike Shubhankar , Cheng Cho-Chin , Feuerherd Martin , Velkov Stoyan , Baldassi Domizia , Afridi Suliman Qadir , Porras-Gonzalez Diana , Wei Xin , Hagen Philipp , Kneidinger Nikolaus , Stoleriu Mircea Gabriel , Grass Vincent , Burgstaller Gerald , Pichlmair Andreas , Merkel Olivia M , Ko Chunkyu , Michler Thomas
Published: December 2021

A promising approach to tackle the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) could be small interfering (si)RNAs. So far it is unclear, which viral replication steps can be efficiently inhibited with siRNAs. Here, we report that siRNAs can target genomic RNA (gRNA) of SARS-CoV-2 after cell entry, and thereby terminate replication before start of transcription and prevent virus-induced cell death. Coronaviruses replicate via negative sense RNA intermediates using a unique discontinuous transcription process. As a result, each viral RNA contains identical sequences at the 5′ and 3′ end. Surprisingly, siRNAs were not active against intermediate negative sense transcripts. Targeting common sequences shared by all viral transcripts allowed simultaneous suppression of gRNA and subgenomic (sg)RNAs by a single siRNA. The most effective suppression of viral replication and spread, however, was achieved by siRNAs that targeted open reading frame 1 (ORF1) which only exists in gRNA. In contrast, siRNAs that targeted the common regions of transcripts were outcompeted by the highly abundant sgRNAs leading to an impaired antiviral efficacy. Verifying the translational relevance of these findings, we show that a chemically modified siRNA that targets a highly conserved region of ORF1, inhibited SARS-CoV-2 replication ex vivo in explants of the human lung. Our work encourages the development of siRNA-based therapies for COVID-19 and suggests that early therapy start, or prophylactic application, together with specifically targeting gRNA, might be key for high antiviral efficacy.
Phase I study using crenolanib to target PDGFR kinase in children and young adults with newly diagnosed DIPG or recurrent high-grade glioma, including DIPG
Authors: Tinkle Christopher L , Broniscer Alberto , Chiang Jason , Campagne Olivia , Huang Jie , Orr Brent A , Li Xiaoyu , Patay Zoltan , Zhang Jinghui , Baker Suzanne J , Merchant Thomas E , Jain Vinay , Onar-Thomas Arzu , Stewart Clinton F , Wetmore Cynthia , Gajjar Amar
Published: December 2021

Background

Platelet-derived growth factor receptor (PDGFR) signaling has been directly implicated in pediatric high-grade gliomagenesis. This study evaluated the safety and tolerability of crenolanib, a potent, selective inhibitor of PDGFR-mediated phosphorylation, in pediatric patients with high-grade glioma (HGG).

Methods

We used a rolling-6 design to study the maximum tolerated dose (MTD) of once-daily crenolanib administered during and after focal radiation therapy in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG) (stratum A) or with recurrent/progressive HGG (stratum B). Pharmacokinetics were studied during the first cycle at the first dose and at steady state (day 28). Alterations in PDGFRA were assessed by Sanger or exome sequencing and interphase fluorescence in situ hybridization or single nucleotide polymorphism arrays.

Results

Fifty evaluable patients were enrolled in the 2 strata, and an MTD of 170 mg/m2 was established for both. Dose-limiting toxicities were primarily liver enzyme elevations and hematologic count suppression in both strata. Crenolanib AUC0–48h and CMAX did not differ significantly for crushed versus whole-tablet administration. Overall, PDGFRA alterations were observed in 25% and 30% of patients in stratum A and B, respectively. Neither crenolanib therapy duration nor survival outcomes differed significantly by PDGFRA status, and overall survival of stratum A was similar to that of historical controls.

Conclusions

Children tolerate crenolanib well at doses slightly higher than the established MTD in adults, with a toxicity spectrum generally similar to that in adults. Studies evaluating intratumoral PDGFR pathway inhibition in biomarker-enriched patients are needed to evaluate further the clinical utility of crenolanib in this population.
Quantitative cerebrospinal fluid circulating tumor cells are a potential biomarker of response for proton craniospinal irradiation for leptomeningeal metastasis
Authors: Wijetunga N Ari , Boire Adrienne , Young Robert J , Yamada Yoshiya , Wolden Suzanne , Yu Helena , Kris Mark , Seidman Andrew , Betof-Warner Allison , Diaz Maria , Reiner Anne , Malani Rachna , Pentsova Elena , Yang Jonathan T
Published: December 2021

Background

Leptomeningeal metastasis (LM) involves cerebrospinal fluid (CSF) seeding of tumor cells. Proton craniospinal irradiation (pCSI) is potentially effective for solid tumor LM. We evaluated whether circulating tumor cells (CTCs) in the CSF (CTCCSF), blood (CTCblood), and neuroimaging correlate with outcomes after pCSI for LM.

Methods

We describe a single-institution consecutive case series of 58 patients treated with pCSI for LM. Pre-pCSI CTCs, the change in CTC post-pCSI (Δ CTC), and MRIs were examined. Central nervous system progression-free survival (CNS-PFS) and overall survival (OS) from pCSI were determined using Kaplan Meier analysis, Cox proportional-hazards regression, time-dependent ROC analysis, and joint modeling of time-varying effects and survival outcomes.

Results

The median CNS-PFS and OS were 6 months (IQR: 4–9) and 8 months (IQR: 5–13), respectively. Pre-pCSI CTCCSF < 53/3mL was associated with improved CNS-PFS (12.0 vs 6.0 months, P < .01). Parenchymal brain metastases (n = 34, 59%) on pre-pCSI MRI showed worse OS (7.0 vs 13 months, P = .01). Through joint modeling, CTCCSF was significantly prognostic of CNS-PFS (P < .01) and OS (P < .01). A Δ CTC-CSF≥37 cells/3mL, the median Δ CTC-CSF at nadir, showed improved CNS-PFS (8.0 vs 5.0 months, P = .02) and further stratified patients into favorable and unfavorable subgroups (CNS-PFS 8.0 vs 4.0 months, P < .01). No associations with CTCblood were found.

Conclusion

We found the best survival observed in patients with low pre-pCSI CTCCSF and intermediate outcomes for patients with high pre-pCSI CTCCSF but large Δ CTC-CSF. These results favor additional studies incorporating pCSI and CTCCSF measurement earlier in the LM treatment paradigm.
1. The Relationship Between Chlorhexidine Skin Concentration and Multidrug-Resistant Organism (MDRO) Colonization in ICU Patients
Authors: Miller Loren G , Richter Stefan , Flores Evelyn A , Ceja Sandra , Torres Crystal , Tran Donna Phan , Salcido Samantha , Tchakalian Gregory , Bloomfield Leah , Gomez Angela , Pham Tuyen , Tong Oanh K , Nutkiewicz Max , Bolaris Michael , McKinnell James A
Published: December 2021

Background

Daily bathing of ICU patients with chlorhexidine gluconate (CHG) is an important method for healthcare-associated infection prevention. We set out to understand the relationship between CHG concentrations and MDRO colonization

Methods

In our trauma/surgical ICU at a large urban medical center, we performed CHG concentrations 2 days/week at 4 times points relative to CHG bathing (Medline, Northfiled, IL) application: 30 min. prior, and 30 min., 6 hrs., and 12 hrs. after application. CHG testing was done at 4 body sites: lateral neck, anterior chest, arm, and inguinal fold. On the contralateral side we tested the presence of the following 4 MDROs: methicillin resistant S. aureus (MRSA), and 3 enteric bacteria--extended spectrum beta-lactamase (ESBL)+ gram-negative rods, vancomycin resistant enterococcus (VRE), and carbapenem resistant enterobacteriaceae (CRE).

Results

We performed testing for 256 patient-days total, of which 42 were swabbed 1 time, 38 swabbed twice, 79 swabbed 3 times, and 97 swabbed 4 times (patient movement for tests, ICU transfer were limitations). Mean CHG skin concentrations were above the MICs of pathogens at all post-CHG application time points at all body sites at all times points (Figure) and decreased during the time points after bathing. In a logistic regression model controlling for patient characteristics, MRSA detection was inversely associated with CHG concentration with an 18% increase in odds of recovery for each 2-fold decrease in CHG concentration, as well as presence of a GI device and lack of ability to sit and roll. In a logistic regression model controlling for patient characteristics, resistant enteric bacteria detection was inversely associated with CHG concentration with an 11% increase in odds of recovery for each 2-fold decrease in CHG concentration, as well as mechanical ventilation, GI device, central line, and ICU duration.

Conclusion

In our large study of CHG use and its association with MDRO detection, CHG concentrations decreased during the 24 hours after application, but were typically above concentrations considered adequate to kill MDROs. CHG concentration were inversely associated with the presence of MRSA and resistant enterics, suggesting that CHG application quality is a key component of the CHG bathing process.

Disclosures

Loren G. Miller, MD, MPH, Medline (Grant/Research Support, Other Financial or Material Support, Contributed product) Stryker (Other Financial or Material Support, Contributed product) Xttrium (Other Financial or Material Support, Contributed product) James A. McKinnell, MD, Medline (Grant/Research Support)
6. Staphylococcus aureus in a Single Blood Culture Bottle: Should We be Concerned?
Authors: Go John Raymond U , Challener Douglas , Corsini Campioli Cristina G , Sohail Muhammad R , Palraj Raj , Baddour Larry M , Saleh Omar Abu
Published: December 2021

Background

Staphylococcus aureus bacteremia (SAB) is common and is characterized by high rates of morbidity and mortality. The clinical importance of a single positive blood culture bottle (SPBCB), however, is poorly defined despite it being a frequent laboratory finding. We therefore examined patients with SPBCB to determine its clinical significance and to understand the rationale of current practice.

Methods

We performed a retrospective, multicenter study of patients with a SPBCB for S. aureus in initial cultures from January 2019 to December 2019 using data collected from both electronic health records and the clinical microbiology laboratory.

Results

Overall, 534 patients with SAB were identified, and 118 (22.1%) had a SPBCB. Among SPBCB cases, 106 (89.3%) were classified as clinically significant while 12 were considered contaminated or of unclear clinical significance. Baseline characteristics were similar between the groups (Table 1). A majority (92.4%) received antibiotic therapy, but patients with clinically significant bacteremia were treated with a longer antibiotic course (25.9 vs 5.7 days, p< 0.001). Outcomes between those with SPBCB (contaminant vs clinically significant) were similar (Table 2). Of note, while there was no difference in use of echocardiography based on PREDICT criteria between the clinically significant SPBCB vs. the multiple positive blood culture bottles (MPBC) cohorts (Table 3), significant differences were seen in both frequency of echocardiography (65.1% vs. 84.6%, P< 0.001) and IE diagnosis (3.8% vs. 14.2%, P=0.002) for patients in the SPBCB vs. MPBC groups, respectively. In addition, those with MPBC had higher 90-day, 6-month and 1-year mortality rates.

Conclusion

SPBCB was documented in almost one-quarter of SAB cases and should trigger a thorough investigation as its associated mortality was high and complications, including IE, occurred. Although some SPBCB cases may represent contamination, antibiotic treatment of SPBCB was commonplace. Patients with clinically significant SPBCB were less likely to undergo echocardiography and had a reduced prevalence of an IE diagnosis as compared to those with MPBC. Patients with SPBCB may have a more favorable long-term prognosis as compared to that in patients with MPBC.

Disclosures

Muhammad R. Sohail, MD, Medtronic (Consultant)Philips (Consultant) Larry M. Baddour, MD, Boston Scientific (Individual(s) Involved: Self): Consultant; Botanix Pharmaceuticals (Individual(s) Involved: Self): Consultant; Roivant Sciences (Individual(s) Involved: Self): Consultant
7. Clinical outcomes and epidemiological characteristics of bacteremia in the older population of Japan
Authors: Nakamura Keiji , Hayakawa Kayoko , Tsuzuki Shinya , Ide Satoshi , Nomoto Hidetoshi , Nakamoto Takato , Yamada Gen , Yamamoto Kei , Ohmagari Norio
Published: December 2021

Background

Japan is one of the most aging societies worldwide. Because older people are highly susceptible to infectious diseases, the characteristics and clinical consequences of bacteremia in this population need clarification.

Methods

Patients aged ≥ 65 years with positive blood cultures were included in this study conducted between April 1, 2015 and March 31, 2018, and divided into three groups: pre-old (65–74 years), old (75–89 years), and super-old (≥90 years) according to the criteria of the Japanese Society of Geriatrics. They were also classified based on medical exposure: community-acquired (CA), healthcare-associated (HCA), and hospital-onset (HO). Parameters retrieved from medical records were used to compare each group using the chi-square test or Fisher’s exact test; factors related to mortality were identified using multivariate logistic regression analysis after controlling for the confounding effect of baseline characteristics and underlying diseases. The Bonferroni corrected P < 0.05 was deemed to be statistically significant.

Results

Overall, 1716 cases of bacteremia were identified in 1415 patients. Of these, 505 cases (29.4%) were found to be due to contamination. Of the 1211 cases without contamination, 397 (32.8%) included pre-old, 658 (54.3%) included old, and 156 (12.9%) included super-old patients. HCA bacteremia increased with age, while HO bacteremia was most common in pre-old patients. Escherichia coli bacteremia was most common in super-old patients. While a central line-associated bloodstream infection was more common in pre-old patients, a urinary tract infection was more common in old and super-old patients. The 7-day mortality was 7.4%, 5.8%, and 14.2% in the pre-old, old, and super-old groups, respectively (P = 0.002). The 7-day mortality for CA, HCA, and HO bacteremia was 5.4%, 6.6%, and 9.5%, respectively (P > 0.05). Multivariate logistic regression showed that HO bacteremia (aOR: 1.76 [1.05–2.94], P = 0.028) and increasing age (aOR: 1.03 [1–1.06], P=0.038) are independent risk factors for 7-day mortality.

Table Comparison of characteristics of bacteremia among the pre-old, old, super-old groups, n (%)

Conclusion

The epidemiology of bacteremia differs among different older age groups; thus, these populations should not be treated as a single entity. A careful approach is needed for the optimal management of bacteremia in them.

Disclosures

All Authors: No reported disclosures
8. Sepsis-Associated Acute Kidney Injury and Acute Kidney Disease: A 15-Year Cohort Study of 4,226 Adult Sepsis Inpatient Survivors at a Tertiary Medical Center in Taiwan
Authors: Liang Chih-Chia , Yeh Hung-Chieh , Chen Pei-Shan , Kuo Chin-Chi , Chiang Hsiu-Yin
Published: December 2021

Background

Sepsis is the most common cause of acute kidney injury (AKI) and about one-third of patients with sepsis-associated AKI (SA-AKI) develop acute kidney diseases (SA-AKD) and may progress to unfavorable outcomes. We aimed to study the characteristics and outcomes associated with SA-AKI and SA-AKD.

Methods

This cohort study included adult inpatients with first-time sepsis who were admitted during 2003-2017, had qualifying serum creatinine (SCr) measurements at baseline (-365 to -3 days), -2 to +7 days, and +8 to +90 days of sepsis index day, and survived the first 90 days (Figure 1). Sepsis was identified using an electronic medical records-based Sepsis-3 criteria. We classified sepsis inpatients into SA-AKI(-), SA-AKD(-), SA-relapsed-AKD, and SA-nonrecovery-AKD (Figure 2). ESRD and mortality were ascertained by linking to the Catastrophic Illness records and to National Death Registry, respectively. Multivariable Cox proportional hazard model was used to evaluate the risk of mortality and end-stage renal disease (ESRD) associated with SA-AKI/AKD subtypes.

Figure 1. Flowchart of the selection process of adult sepsis survivors (N = 4226 patients).

Figure 2. Definitions of sepsis associated-acute kidney injury (SA-AKI) and sepsis associated-acute kidney disease (SA-AKD).

Results

Of 4,226 eligible sepsis inpatient survivors, 47.1% developed SA-AKI and 10.1% progressed to SA-AKD (5.4% relapsed and 4.7% nonrecovery). Patient with AKI and non-recovered AKD had the worst baseline renal function (SCr, 1.3 mg/dL) (Table 1). The multivariable analyses revealed that SA-relapsed AKD was significantly associated with increased risk of all-cause mortality for 1-year (aHR 1.67; 95% CI 1.25, 2.24), 3-year (aHR 1.38; 95% CI 1.11, 1.71), and overall (aHR 1.35; 95% CI 1.12, 1.61), compared with SA-AKI(-). SA-relapsed AKD and SA-nonrecovery AKD were both significantly associated with 1-year, 3-year, and overall ESRD, with the risk of about 4-fold or higher than SA-AKI(-) (Table 2).

Table 1. Baseline characteristics and outcomes among adult sepsis survivors, by different SA-AKI/AKD subtypes.

Table 2. Risk of all-cause mortality and end stage renal disease (ESRD) among adult sepsis survivors.

Conclusion

Sepsis survivors who initially had AKI and developed relapsed or nonrecovery AKD tended to have worse outcomes of all-cause and ESRD, compared with those without AKI. Unexpectedly, patients with non-recovered AKD did not have a higher mortality risk, possibly because we have selected those who survived the first 90 days of sepsis. We will develop two-stage prediction models to identify sepsis patients at risk of developing AKI and SA-AKI patients at risk of developing different types of AKD.

Disclosures

All Authors: No reported disclosures
9. The Skip Phenomenon in Staphylococcus aureus Bacteremia: Clinical Associations
Authors: Go John Raymond U , Baddour Larry M , Lahr Brian , Sohail Muhammad R , Palraj Raj
Published: December 2021

Background

Serial blood cultures are integral in managing Staphylococcus aureus bacteremia (SAB) as clinicians rely on the results to determine infectious complication risks and antibiotic duration. Current IDSA guidelines suggest a single set of negative blood cultures is adequate evidence of SAB clearance. Several studies, however, have identified the skip phenomenon (SP), which is the occurrence of intermittent negative blood cultures, and have recommended obtaining additional blood cultures to document bacterial clearance (Table 1). We therefore examined patients who manifested the SP to determine its clinical significance and to study this, associations were tested for SP in relation to various baseline factors as well as clinical outcomes.

Methods

We performed a retrospective, multicenter study of all patients with a positive blood culture for S. aureus from January 2019 to December 2019 using data collected from electronic health records and the clinical microbiology laboratory.

Results

A total of 602 patients with SAB were identified and 495 patients were included in the investigation (Figure 1). Overall, 25 (5.1%) patients had the SP. Significant differences between those who did and did not manifest the SP included higher rates of injection drug use, automatic implantable cardioverter defibrillator, and community onset of infection in the SP cohort (Table 2). Moreover, the median duration of SAB was longer (3.2 [2.3-5.4] vs 1.90 [1.2-2.9] days, p=0.002), and high-grade SAB, (88.0% vs 58.7%, p=0.004), complicated bacteremia (92.0% vs 67.9%, p=0.011) and IE diagnosis (28.0% vs 11.3%, p=0.013) were all more common in the SP group. In unadjusted outcome analyses, association of SP with hospital length of stay was not significant, although a higher risk of in-hospital mortality among SP patients approached statistical significance (p=0.055). Analysis of 435 hospital survivors revealed no significant differences in rates of 1-year mortality or 90-day relapse between the two groups (Table 3).

Conclusion

Findings of the current investigation demonstrates an increased risk of SAB complications in patients with the SP and support the notion that serial negative blood cultures are needed to document clearance of SAB.

Disclosures

Larry M. Baddour, MD, Boston Scientific (Individual(s) Involved: Self): Consultant; Botanix Pharmaceuticals (Individual(s) Involved: Self): Consultant; Roivant Sciences (Individual(s) Involved: Self): Consultant Muhammad R. Sohail, MD, Medtronic (Consultant)Philips (Consultant)
10. Impact of Infectious Disease Consultation and Theoretical Management Bundle in Patients with Candidemia
Authors: Adeghe ifueko J , Kabbani Dima , Dingle Tanis C , Chen Justin
Published: December 2021

Background

Candidemia is associated with significant morbidity and mortality. The impact of infectious diseases consultation (IDC) on clinical outcomes in patients with candidemia is not well established. We evaluated the impact of IDC and a management bundle on clinical outcomes in patients with candidemia.

Methods

A retrospective chart review of adult (age ≥ 18 years) patients with at least 1 blood culture growing Candida species identified at Alberta Precision Laboratories between December 1, 2019 to November 30, 2020 and hospitalized at the University of Alberta Hospital, Edmonton, Canada were included. Patients who died within 48 hours and those who left against medical advice within 24 hours of initial positive blood culture result were excluded. Demographics, management, and outcome data were collected. A complete management bundle was defined as having all the following elements performed: IDC, repeat blood cultures, empiric echinocandin therapy, ophthalmology consult, and echocardiogram.

Results

Thirty-one patients were included for study; mean age was 56 ± 17 years and 65% were male. 14 (45%) cases were admitted under critical care, 7 (23%) surgery, and 10 (32%) medicine. 3/17 (18%) required intensive care unit admission following candidemia diagnosis. Candida albicans was identified in more than half the cases. The primary source was intra-abdominal in 12 (39%), central-line associated in 8 (26%), and urinary in 6 (19%). IDC occurred in 27 cases (87%), echocardiogram in 22 (71%), ophthalmology consult in 10 (32%), and follow-up blood cultures in 30 (97%). 20 (65%) patients received empiric echinocandin. Of the remainder who received empiric fluconazole, 4 (36%) grew non albicans Candida species.

Higher in-hospital mortality was observed in cases without IDC than those with IDC (4/4, 100% vs 8/27, 29.6%, p=0.016) and in those that did not have a complete bundle (12/25, 48% vs 0/6, p=0.059). However, IDC was not associated with the receipt of individual bundle components nor the complete bundle (p=NS).

Conclusion

In patients with candidemia, lower in-hospital mortality was observed in patients who received IDC. Larger studies are required to confirm our findings and assess whether the implementation of a candidemia management bundle is beneficial.

Disclosures

Dima Kabbani, MD, AVIR Pharma (Grant/Research Support, Other Financial or Material Support, Speaker)Edesa Biotech (Scientific Research Study Investigator)Merck (Scientific Research Study Investigator)
12. Development of Provider-Specific Antibiotic Prescribing Feedback for Inpatient Antibiotic Stewardship Programs in Veterans Affairs (VA) Facilities (ASP)
Authors: Goetz Matthew B , Goetz Matthew B , Fang Michelle , Calub Feliza , Belperio Pamela , Stevens Vanessa W , Hicks Lauri , Srinivasan Arjun , Srinivasan Arjun , Jones Barbara E , Neuhauser Melinda M , Jones Makoto M
Published: December 2021

Background

Provision of provider-specific outpatient antibiotic prescribing data has resulted in significant decreases in antibiotic use. We describe the development of reports of inpatient antibiotic prescribing by hospitalists attending on acute medical wards in VA medical facilities.

Methods

We created algorithms for determining the attending physician responsible for patient days present (DP), by considering changes of service (e.g., prior to admission from the emergency department) and transfers between services or physicians. Each antibiotic dose was assigned to a single attending, ward location, and service according to denominator assignment. Antibiotic use was grouped into Centers for Disease Control and Prevention drug categories and expressed as antibiotic days of therapy (DOT) per 1000 DP. Data were obtained from the VA Corporate Data Warehouse. Algorithms were iteratively refined based on reviews of medical records from three VA medical centers and applied to acute care patients at a single site for 2018-2020.

Results

In 2018-2020, 294 attendings oversaw acute inpatient care for >= 14 DP. 129 attendings with >= 300 DP oversaw 88.0% of all patient care and prescribed 87.6% of all antibiotics (480 DOT/1000 DP, IQR 375-559), 90.1% of broad-spectrum therapy for hospital-onset infections (55 DOT/1000 DP, IQR 31-72) and 88.3% of resistant Gram-positive therapy (70 DOT/1000 DP, IQR 39-89) in inpatient wards. The distribution of antibiotic use for acute care ward patients amongst these 129 staff is shown in the following figure.

Conclusion

We developed algorithms to attribute antibiotic therapy to inpatient attendings that can be broadly applied in facilities with electronic medical records. As with outpatient prescribing, we found large variation across inpatient attendings in overall antibiotic use and broad-spectrum antibiotic use. In future work, we will obtain provider feedback of report usability and interpretability and assess whether distribution of these reports allows antibiotic stewards to favorably influence provider prescribing practices.

Disclosures

Matthew B. Goetz, MD, Nothing to disclose Arjun Srinivasan, MD, Nothing to disclose
16. Attributable Mortality, Healthcare Costs and Out-of-Pocket Costs of Clostridioides difficile Infection in US Medicare Advantage Enrollees
Authors: Yu Holly , Nguyen Jennifer L , Alfred Tamuno , Zhou Jingying , Olsen Margaret A
Published: December 2021

Background

US attributable CDI mortality and cost data are primarily from Medicare fee-for-service populations. Little is known about Medicare Advantage Enrollees (MAEs), who comprise about 39% of the Medicare population.

Methods

Using 2017‒2019 Optum’s de-identified Clinformatics® Data Mart database, this retrospective cohort study identified first C difficile infection (CDI) episodes occurring in 2018 among eligible MAEs ≥66 y of age who were continuously enrolled for 12 mo before CDI diagnosis (baseline period). CDI was defined via ICD10 diagnosis codes or evidence of toxin testing with CDI antibiotic treatment. To assess all-cause mortality and CDI-associated healthcare and patient out-of-pocket (OOP) costs, CDI+ cases were matched 1:1 to CDI– controls using propensity scores (PS) and were followed through the earliest of death, disenrollment or end of the 12 mo followup. Additionally, outcome analyses were stratified by infection acquisition and hospitalization status.

Results

Among 3,450,354 eligible MAEs, 15,195 (0.4%) had a CDI episode in 2018. Using PS generated from >60 variables collected in the baseline period, 14,928 CDI+ cases were matched to CDI– controls.

Over 12 mo of follow-up, the difference in 1-y attributable mortality was 7.9% in the CDI+ (26.3%) vs CDI– (18.4%) cohort (Figure 1). CDI-attributable mortality was higher among hospitalized CDI+ cases (18.4% for healthcare associated [HA]; 13.1% for community associated [CA]) vs nonhospitalized CDI+ cases (HA, 4.5%; CA, 1.0%).

Similarly, healthcare costs were higher for CDI+ vs CDI– patients, with excess mean total cost of &13,363 at the 2-mo follow-up (Figure 2). Total excess mean healthcare costs were greater among hospitalized CDI+ patients (HA, &28,139; CA, &28,136) than for nonhospitalized CDI+ patients (HA, &5741; CA, &2503). CDI-associated excess mean OOP cost was &409 for CDI+ cases at the 2 mo followup. Total excess mean OOP cost was highest in CA hospitalized CDI+ cases, followed by HA hospitalized CDI+ cases, HA nonhospitalized CDI+ cases and finally CA nonhospitalized CDI+ cases (&964, &574, &231 and &197, respectively).

Conclusion

CDI is associated with major mortality and total healthcare and OOP costs. Preventing CDI in the elderly may improve outcomes and reduce costs for healthcare systems and patients.

Disclosures

Holly Yu, MSPH, Pfizer Inc (Employee, Shareholder) Jennifer L Nguyen, ScD, MPH, Pfizer Inc. (Employee) Tamuno Alfred, PhD, Pfizer Inc. (Employee) Jingying Zhou, MA, MEd, Pfizer Inc (Employee, Shareholder) Margaret A. Olsen, PhD, MPH, Pfizer (Consultant, Research Grant or Support)
18. Global Surveillance of Clostridioides difficile Demonstrates High Prevalence in Non-Healthcare Settings
Authors: Jo Jinhee , Gonzales-Luna Anne J , Garey Kevin W
Published: December 2021

Background

Clostridioides difficile is a Gram-positive, spore-forming, toxin-producing organism that is the leading cause of healthcare-associated infections. However, past studies have isolated C. difficile spores from the community, suggesting an environmental reservoir that may play a role in transmission. This study aimed to examine the prevalence and strain types of C. difficile isolated from the United States (US) and internationally.

Methods

From 2014 to 2017, environmental swabs were collected from public areas, healthcare settings, and shoe soles. Samples were considered positive for C. difficile following growth on CCFA plates and confirmatory PCR testing for toxin genes and fluorescent PCR ribotyping (RT). The rate of C. difficile positivity and associated RT distribution were compared between settings, including shoe soles which were investigated for their potential role in environmental transmission.

Results

A total of 11,986 unique isolates were obtained primarily from the US (n=11,002; 92%) in addition to 11 other countries including Taiwan (n=200) and India (n=187). Samples were categorized as being from outdoor environments (n=2,992), private residences (n=2,772), shoe soles (n=1,420), public buildings (n=1,104) or acute care settings (n=3,698). Worldwide C. difficile sample positivity was 26% and was similar between US and non-US sampling sites. In the US, private residences (26.2%) and outdoor environments (24.1%) had the highest positivity rate compared to public buildings (17.2%). In a Texas sub-analysis (n=8,571), positivity rates were highest from outdoor samples (27%) and were similar between private residences (24%) and healthcare buildings (24%). The most prevalent RTs overall were F014-020 (16.4%), F106 (14.9%), and FP310 (11%). Shoe soles had the highest positivity rate (45%) with similar RT distribution between shoe soles and environmental samples.

Conclusion

Using a worldwide sample, 26% of environmental samples tested positive for toxigenic C. difficile strains from healthcare and non-healthcare sites. Community stewardship efforts will be needed to reduce the risk of CDI in vulnerable patients. Shoe sole sampling may be an ideal surveillance tool to test for emerging epidemic strains.

Disclosures

Kevin W. Garey, Pharm.D., M.S., FASHP, Summit Therapeutics (Research Grant or Support)
23. Development and Validation of a Risk Score for Post-transplant Lymphoproliferative Disorders among Solid Organ Transplant Recipients
Authors: dos Santos Quenia , Wareham Neval E , Mocroft Amanda , Rasmussen Allan , Gustafsson Finn , Perch Michael , Sørensen Søren Schwartz , Manuel Oriol , Mueller Nicolas , Lundgren Jens , Reekie Joanne
Published: December 2021

Background

Post-transplant lymphoproliferative disease (PTLD) is a well-recognized complication after transplant. This study aimed to develop and independently validate a risk score to predict PTLD among solid organ transplant (SOT) recipients (kidney, liver, lung and heart).

Methods

Poisson regression identified predictors of PTLD with the best fitting model selected for the risk score, where each predictor contributed with a risk coefficient to the risk score, dividing patients in high vs low risk of having a PTLD.

Results

For both cohorts, most of the patients were male, aged more than 16 years old, kidney recipients and with a low-risk pre-transplant Epstein-Barr Virus (EBV) IgG donor/recipient serostatus. The derivation cohort consisted of 2546 SOT transplanted at Rigshospitalet, Copenhagen between 2004-2019; 57 developed PTLD. Predictors of PTLD were high-risk pre-transplant Epstein-Barr Virus (EBV) IgG donor/recipient serostatus, and current plasma EBV DNA positive, abnormal hemoglobin and C-reactive protein levels. A positive EBV DNA was the strongest parameter for the PTLD risk score (figure 1), although the model was able to predict the risk of PTLD cases in both EBV positive and EBV negative individuals. Individuals in the high-risk group had almost 7 times higher incidence of PTLD compared to the low risk group (table 1). In the validation cohort of 1611 SOT recipients between 2008-2018 from University Hospital of Zürich, 24 developed PTLD. A similar seven times higher risk of PTLD was observed in the high-risk group compared to the low risk group (table 1). The discriminatory ability was also similar in derivation (Harrell’s C-statistic of 0.82 95%CI (0.76-0.88) and validation (0.82, 95% CI:0.72-0.92) cohorts.

An explanation about how the risk for PTLD is calculated for the SOT recipients; in this example the risk of developing PTLD is calculated in the next 180 days

Performance of the PTLD score in the derivation and validation cohorts (low-risk group: score<=17 points; high-risk group: score>17 points)

Conclusion

The risk score had a good discriminatory ability in both cohorts and helped to identify patients with higher risk of developing PTLD, so they can be monitored more often. This is the first risk-score developed and externally validated to predict risk of PTLD among SOT recipients.

Disclosures

All Authors: No reported disclosures
26. Risk of Post–COVID-19 Dyspnea and Interstitial Lung Disease (ILD) in a Real-World Cohort of Patients Hospitalized with COVID-19 in the United States
Authors: Zalocusky Kelly , Chawla Devika , Neighbors Margaret , Rizzo Shemra , Tsai Larry
Published: December 2021

Background

While COVID-19 carries substantial morbidity and mortality, the extent of long-term complications remains unclear. Reports suggest that acute lung damage associated with severe COVID-19 can result in chronic respiratory dysfunction. This study: (1) estimated the incidence of dyspnea and ILD after COVID-19 hospitalization, and (2) assessed risk factors for developing dyspnea and ILD in a real-world cohort of patients hospitalized with COVID-19 using US electronic health records (EHR).

Methods

Patients in the Optum de-identified COVID-19 EHR database who were hospitalized for COVID-19 (lab confirmed or diagnosis code) between February 20 and July 2020 and had at least 6 months of follow-up were eligible for analysis. Dyspnea and ILD were identified using diagnosis codes. The effects of baseline characteristics and hospitalization factors on the risk of incident dyspnea or ILD 3 to 6 months’ post discharge were evaluated.

Results

Among eligible patients (n=26,339), 1705 (6.5%) had dyspnea and 220 (0.8%) had ILD 3 to 6 months after discharge. Among patients without prior dyspnea or ILD (n=22,613), 110 (0.5%) had incident ILD (Table 1) and 1036 (4.6%) had incident dyspnea (Table 2) 3 to 6 months after discharge. In multivariate analyses, median (IQR) length of stay (LOS; 5.0 [3.0, 9.0] days in patients who did not develop ILD vs 14.5 [6.0, 26.0] days in patients who developed ILD; RR: 1.12, 95% CI: 1.08, 1.15; P=4.34 x 10-10) and age (RR: 1.02, 95% CI: 1.01, 1.03; P=4.63 x 10-3) were significantly associated with ILD. Median (IQR) LOS (5.0 [3.0, 9.0] days in patients who did not develop dyspnea vs 7 [4.0, 14.0] days in patients who developed dyspnea; RR: 1.04, 95% CI: 1.02, 1.06; P=8.52 x 10-4), number of high-risk comorbidities (RR: 1.18, 95% CI: 1.12, 1.24; P=3.85 x 10-9), and obesity (RR: 1.52, 95% CI: 1.25, 1.86; P=2.59 x 10-4) were significantly associated with dyspnea.

Table 1. Selected Baseline Risk Factors for Incident ILD

Table 2. Selected Baseline Risk Factors for Incident Dyspnea

Conclusion

In a real-world cohort, 4.6% and 0.5% of patients developed dyspnea and ILD, respectively, after COVID-19 hospitalization. Multivariate analyses suggested that LOS, age, obesity, and comorbidity burden may be risk factors for post-COVID-19 respiratory complications. Limitations included sensitivity of diagnosis codes, availability of labs, and care-seeking bias.

Disclosures

Kelly Zalocusky, PhD, F. Hoffmann-La Roche Ltd (Shareholder)Genentech, Inc. (Employee) Devika Chawla, PhD MSPH, F. Hoffmann-La Roche Ltd. (Shareholder)Genentech, Inc. (Employee) Margaret Neighbors, PhD, F. Hoffmann-La Roche Ltd (Shareholder)Genentech, Inc. (Employee) Shemra Rizzo, PhD, F. Hoffmann-La Roche Ltd. (Shareholder)Genentech, Inc. (Employee) Larry Tsai, MD, F. Hoffmann-La Roche Ltd (Shareholder)Genentech, Inc. (Employee)
28. Utilizing the Charleston Comorbidity Index as an Independent Predictor for Outcomes in SARS-Cov-2 Positive Patients
Authors: Guiance Irene Riestra , Char Steven , Gonzaga Ernesto Robalino , Riestra Isabel , Ho Minh Q
Published: December 2021

Background

Since COVID-19 was declared a pandemic, it has seemed that the virus is nondiscriminatory causing 3.73 million deaths worldwide. The Charleston Comorbidity Index (CCI) is a scoring system predicting the one-year mortality for patients with a range of comorbid conditions and is widely used as a predictor of prognosis and survival for a range of pathologies. This study aims to assess if there is an impact of comorbidity burden on COVID-19 patients by utilizing their CCI score.

Charleston Comorbidity Index Score

Scoring system for Charleston Comorbidity Index (CCI). Plus 1 point for every decade age 50 years and over, maximum 4 points. Higher scores indicate a more severe condition and consequently, a worse prognosis.

Methods

Multicenter, retrospective review of patients diagnosed with COVID-19 from January 2020 to September 2020 throughout the HCA Healthcare system. CCI scores for all COVID-19 positive patients were calculated and logistic regression analysis was performed to predict hospitalization and ICU admission by CCI controlling for age, sex and race. A multinomial regression model was also performed to predict discharge status by CCI controlling for age, sex and race. ROC curves to indicate the CCI cut-off point for each outcome (hospitalization, ICU admission and mortality) was performed, and Youden’s Index was used to identify the optimal point.

Results

In the study timeframe, 92,800 patients were diagnosed with COVID-19 and of those, 48,270 were hospitalized. A one-point increase in CCI was associated with higher odds of hospitalization [OR 1.718; 95% CI 1.696-1.74]. The threshold for significance to predict hospitalization was a CCI of 1.5 (AUC 0.804, Youden Index 0.48) with a specificity (73%) and sensitivity (75%). A one-point increase in CCI was associated with 1.444 higher odds of an ICU admission (95% CI 1.134-1.155). A one-point increase in CCI significantly increased the odds of discharge to hospice compared to any discharge other than hospice [OR 1.162; 95% CI 1.142-1.182]). A one-point increase in CCI score was associated with 1.188 higher odds of in-hospital mortality (95% CI, 1.173-1.203) with a CCI threshold of 3.5 having the highest specificity (50.9%) and sensitivity (79.9%) to predict mortality outcome (AUC 0.704, Youden Index 0.31).

Conclusion

In conclusion CCI score is an adequate predictor of hospitalization and in-hospital mortality but less so in predicting ICU admission in COVID-19 positive patients.

Disclosures

All Authors: No reported disclosures
30. SARS-CoV2 Reinfections in a University Teaching Hospital
Authors: Sutton Una , Lynch Judi , Fitzgerald Niamh , Macori Guerrino , Fanning Séamus , Fennell Jérôme
Published: December 2021

Background

The consequences of SARS-CoV2 reinfections for patients, healthcare workers and society are unclear. We reviewed the clinical, laboratory, and epidemiological characteristics of patients re-infected with genetically distinct strains of SARS-CoV2 identified by Whole Virus Genome Sequencing (WvGS).

Methods

Cases were selected based on a positive SARS-CoV-2 Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) test, clinical resolution, a negative interim test and a subsequent positive nasopharyngeal swab. Positive samples were prepared for sequencing by cDNA synthesis, tiled-PCR following the ARTIC protocol and amplicon sequencing using Illumina MiSeq platform. Raw reads were mapped to the reference sequence using bowtie and Samtools was used for variants calling and to generate the consensus sequences. Comparative sequence analysis was conducted by phylogenetic inference maximum likelihood method with RAxML using the multiple sequence aligned by MAFFT. Clades and variants were assigned respectively using Nextstrain and Pangolin COVID-19 lineage assigner (Figure 1). The clinical, radiological and laboratory data were collected from patient medical notes and laboratory information system.

Results

Two cases of SARS-CoV-2 reinfection were detected by RT-PCR (patient 1 and 2). CT values and strain variants are presented in Table 1. The time between detection of the first and second infection was 67 and 270 days respectively. WvGS confirmed that the second episodes were due to a genetically distinct strain of SARS CoV2. These reflected the dominant contemporaneous variants in circulation.

Both patients were immunocompromised from co-morbidities and medications. First and subsequent infections were minimally symptomatic. Both cases were associated with known hospital outbreaks. They passed away within 2 weeks of the second infection of unrelated causes.

Conclusion

Two patients in this study were diagnosed with a SARS-CoV-2 reinfection confirmed by WvGS. A common factor in these cases was immunocompromise. Where a previously infected patient test shows a new positive or an unexpected reduction in CT value is observed, we recommend individual risk assessment to determine the timing of discontinuation of isolation and infection control precautions.

Disclosures

Jérôme Fennell, MB BCh BAO MSc PhD FRCPath FRCPI, Roche Diagnostics (Advisor or Review Panel member)
31. Development a Novel Score (SAD-60) for Predicting Mortality in Hospitalised Patients with COVID-19 Pneumonia: A Multicenter Retrospective Study of 1013 Patients
Authors: Surme Serkan , Karanalbant Hatice Kubra , Tuncer Gulsah , Bayramlar Osman , Copur Betul , Zerdali Esra , Nakir İnci Yilmaz , Yazla Meltem , Buyukyazgan Ahmet , Cinar Ayse Kurt , Kurekci Yesim , Alkan Mustafa , Ozdemir Yusuf Emre , Sengoz Gonul , Pehlivanoglu Filiz
Published: December 2021

Background

We aimed to explore a novel risk score to predict mortality in hospitalised patients with COVID-19 pneumonia. In additoon, we compared the accuracy of the novel risk score with CURB-65, qSOFA and NEWS2 scores.

Methods

The study was conducted in hospitalised patients with laboratory and radiologically confirmed COVID-19 pneumonia between November 1, 2020 and November 30, 2020. In this retrospective multicenter study. independent predictors were identified using multivariate logistic regression analysis. A receiver operating characteristics (ROC) analysis with area under the curve (AUC) was used to evaluate the performance of the novel score. The optimal cut-off points of the candidate variables were calculated by the Youden’s index of ROC curve. Mortality was defined as all cause in-hospital death.

Results

A total of 1013 patients with COVID-19 were included. The mean age was 60,5 ±14,4 years, and 581 (57,4%) patients were male. In-hospital death was occured in 124 (12,2%) patients. Multivariate analysis revealed that peripheral capillary oxygen saturation (SpO2), albumin, D-dimer, and age were independent predictors for mortality (Table). A novel scoring model was named as SAD-60 (SpO2, Albumin, D-dimer, ≥60 years old). SAD-60 score (0,776) had the highest AUC compared to CURB-65 (0,753), NEWS2 (0,686), and qSOFA (0,628) scores (Figure).

Conclusion

We demonstrated that SAD-60 score had a promising predictive capacity for mortality in hospitalised patients with COVID-19.

Univariate and multivariate analysis of factors predicting mortality

Comparison of CURB-65, qSOFA, NEWS-2 and SAD-60 for predicting pneumonia mortality in hospitalised patients with COVID-19 by ROC analysis

Disclosures

All Authors: No reported disclosures
36. Clinical Features of and Risk Factors for 30-day Readmission after an Initial Hospitalization with COVID-19
Authors: Fukushima Elisa Akagi , Santos Claudia Villatoro , Sharma Mamta , Szpunar Susan M , Saravolatz Louis , Bhargava Ashish
Published: December 2021

Background

Little is known about risk factors for readmission after COVID-19 hospitalizations. Knowledge of these factors may help to identify patients at increased risk and may help to prevent these rehospitalizations.

Methods

This historical cohort study was conducted at a tertiary care academic medical center. We included COVID-19 cases diagnosed by reverse-transcriptase polymerase-chain-reaction (RT-PCR) assay between March 8th and June 14th, 2020. Patients readmitted within 30 days were identified. Using the electronic medical record, we collected data on demographic and clinical information. Data were analyzed using Student’s t-test, the chi-squared test and multivariable logistic regression.

Results

We included 391 patients who survived after the index hospitalization for COVID-19. The readmission rate was 13.3% (52/391). The mean time to readmission was 9.2 ± 7.9 days. The mean age (±SD) was 66.3 ± 18.6 years, 44.2% were male, and 78.8% were black/African-American. The most common presenting complaint was shortness of breath (50%). The most frequent diagnosis during the readmission was infectious process (57.7%). The mortality rate on readmission was 11.5%. Patients with a 30-day readmission were older than those not readmitted, mean age (±SD) 66.3 ± 18.6 vs. 61.0 ± 16.0, respectively (p=0.03). Readmitted patients also had a higher prevalence of heart failure and renal disease as comorbidities. Elevated alanine aminotransferase (AST) and low albumin level were also associated with readmission (Table 1). Intensive care unit (ICU) admission or mechanical ventilation during the index admission did not increase the risk of readmission. From multivariable analysis, independent predictors of 30-day readmission were higher Charlson score (p=0.004), higher creatinine on admission in the index hospitalization (p=0.009), and presence of rhabdomyolysis during the index hospitalization (p=0.039) (Table 2).

Table 1. Univariable Analysis of Predictors for Readmission within 30 days from COVID-19 Infection

Table 2. Multivariable Analysis of Predictors for Readmission within 30 days from COVID-19 Infection

Conclusion

In our cohort, infectious etiologies were common among those readmitted within 30 days of COVID-19. A higher Charlson score, acute renal failure, and rhabdomyolysis during the index admission were independent predictors of a 30-day readmission. Further studies are required to investigate these contributing factors.

Disclosures

All Authors: No reported disclosures