bluuebunny/crossref_metadata_2025_split huggingface dataset:
1095. Retrospective Review of SARS-CoV-2 Infection in Immunocompromised Children at a Single Pediatric Institution
Authors: Khan Aslam , Mathew Roshni , Rosenthal Ayelet 
Published: December 2022

Abstract

Background
Immunocompromised individuals are considered higher risk for severe COVID-19 disease. Much of this data was collected from adults with limited pediatric reporting, although a recent study showed no worse outcome in immunocompromised children. In this study, we characterize our experience of immunocompromised children who were hospitalized with acute SARS-CoV-2 infection and aimed to identify a sub-group of patients who had worse outcomes.

Methods
We reviewed charts of all immunocompromised children hospitalized with SARS-CoV-2 RT-PCR positive results at our hospital from March 2020-April 2022. Disease severity was characterized according to the NIH COVID-19 guidelines. Clinical characteristics and outcomes were assessed. Individuals were grouped into solid organ transplant recipients, solid tumors, liquid tumors, and stem cell transplant recipients. Proportions were calculated per group in addition to the exact binomial confidence intervals (95%).

Results
We identified 39 pediatric aged patients ranging from 7 months to 20 years of age with a median age of 10. 35.9% (14/39) of individuals were solid organ transplant recipients, 25.6% (10/39) had solid tumors, 33% (13/39) had liquid tumors, and 5% (2/39) were stem cell transplant recipients. 17.9% were asymptomatic, 66.7% had mild disease, and 15.4% had severe/critical COVID-19 disease. The median time of positive SARS CoV-2 RT-PCR was 32 days. Six children had prolonged SARS-CoV-2 RT-PCR positive testing between 29-97 days with a mean of 49 days. Viral strand specific RNA testing for replicating virus was also persistently positive. Six experienced severe/critical disease resulting in death of three. Most of the patients were treated with predominantly T cell depleting agents (∼74%). However, four patients who had prolonged active critical infection were treated with B cell depleting agents or had known B cell dysfunction.

Conclusion
The majority of the immunocompromised children in our cohort had mild COVID-19 disease. A subset of individuals experienced ongoing prolonged RT-PCR positivity and testing indicating persistent viral replication, with three demonstrating an inability to control the virus and resulting in death. Worse outcomes may be related to their immune dysfunction and use of B cell depleting agents.

Disclosures
All Authors: No reported disclosures.
1108. Feasibility and Impact of a Monoclonal Antibody Infusion Program in Reaching Vulnerable Underserved Communities
Authors: Mena Lora Alfredo J , Herald Fischer , Lindsey Brenna , Echeverria Stephanie , Li Ella , Sanchez Lawrence , Truesdell Tiffany , Takhsh Eden , Lavani Romeen , Burgos Rodrigo M 
Published: December 2022

Abstract

Background
Monoclonal antibodies (mAbs) against SARS-CoV-2 are potent therapeutics that prevent progression of disease in high-risk patients. Deploying mAb infusion programs and reaching communities in need remains challenging. We established a mAb infusion program centered in the emergency department (ED) fast-track. We seek to assess the feasibility and impact of our mAb infusion program in reaching vulnerable underserved communities.

Methods
The ED fast-track was repurposed for mAb infusions. Indications and protocols were created by the infectious disease (ID) physician and antimicrobial stewardship program (ASP). Test to treat was deployed in the ED and a referral program connected patients from telehealth and providers in the community to the infusion program (Figure 1). Data on mAb use from November 2020 to February 2022 was reviewed. To assess the reach of the program in vulnerable communities, the COVID-19 Community Vulnerability Index (CCVI) map by zip code was used. The CCVI identifies communities at risk by using variables such as sociodemographic variables, occupational factors, cumulative COVID-19 burden, vaccine uptake and other factors. Figure 1.Monoclonal antibody infusion test-to-treat and referral process in the ED fast track

Results
mAbs were successfully deployed and sustained throughout the pandemic, increasing its use in each COVID-19 surge by &gt;103% (Figure 2). A total of 267 patients were treated, with an average age of 52 years, of which 55% (147) were female. Ethnicity was 46% Hispanic and Race was 54% White, 28% Black, 1.4% Asian, 1.8% Multiracial and 14% Other. Zip codes by CCVI were 64% high, 18% medium, and 3% low CCVI index. 15% were outside of city limits without CCVI index (Figure 3). Figure 2.COVID-19 Community Vulnerability Index (CCVI) of patients who received monoclonal antibodies at our program
Figure 3 Monoclonal antibody infusions by COVID-19 Community Vulnerability Index (CCVI) and Zip codes

Conclusion
A mAb infusion program with test to treat and referrals from the community was successfully deployed in an ED fast track. The ED space and staff can be leveraged for mAbs during surges amid clinic staffing challenges. The program adopted novel mAbs as new COVID-19 variants emerged. Uptake increased with each wave, likely reflecting awareness of mAbs and the infusion program by patients and providers in the community. The majority of patients served (82%) were of high and medium CCVI. Thus, this mAb infusion program led by ID and ASP successfully reached predominantly underserved vulnerable populations.

Disclosures
All Authors: No reported disclosures.
1111. Baricitinib versus Tocilizumab for Hospitalized Adults with Severe COVID-19 in a Community Health System: A Retrospective Cohort
Authors: Gonzalez Alexandra , Martinez Aileen , Cardona Lyssette L , Hernandez-Jimenez Jarelys 
Published: December 2022

Abstract

Background
Severe coronavirus disease 2019 (COVID-19) is associated with respiratory failure as well as thromboembolic and cardiovascular complications from dysregulated immune responses. Baricitinib (BAR), a Janus kinase (JAK) inhibitor, and tocilizumab (TZB), a monoclonal anti-interleukin-6 (IL-6) receptor antibody, earned Emergency Use Authorizations (EUA) from the Food and Drug Administration (FDA) for the treatment of COVID-19. This study aims to compare the effects of BAR and TZB in severe COVID-19.

Methods
A retrospective chart review of patients admitted to Cleveland Clinic Martin Health with COVID-19 having received TZB or BAR was completed between 07/01/20 to 12/31/21. Exclusion criteria included patients who had received both agents in the same admission, received fewer than 5 doses of remdesivir, or were pregnant. The primary objective was to evaluate in-hospital mortality. For secondary outcomes, hospital length of stay (LOS), intensive care unit LOS, readmission due to respiratory-related causes, progression to mechanical ventilation (MV) and CRP levels upon discharge or death were assessed. Safety outcomes were described by incidences of superimposed bacterial infections, thrombosis, and herpes simplex virus reactivation.

Results
After adjustment of sex and CRP level, the odds of death in TZB was 86% higher than that of BAR group (OR 1.86, 95%CI 1.17-2.96, p=0.009). TZB group had more females (45% vs. 34%, p=0.036) and longer LOS (median [IQR]: 15 [10,23] vs. 13 [9,20], p=0.0390). TZB group had more organ support (47% vs. 29%, p&lt; 0.001), more ICU admission and longer ICU LOS, more MV progression and longer duration of MV (36% vs. 22%, p=0.007; 0[0,9] vs. 0[0,2], p&lt; 0.001). TZB had more additional source of infection (25% vs. 16%, p=0.043) and more positive microbiology from blood (10% vs. 3%, p=0.009).

Conclusion
Our findings suggest that BAR may have lower rates of in-hospital mortality when compared to TZB. TZB was also found to have higher needs for organ support. Superimposed infections, thrombosis, and HSV reactivation were similar in both groups. Larger randomized studies comparing these agents are needed.

Disclosures
All Authors: No reported disclosures.
1131. Evaluation of drug-drug interaction potential of ensitrelvir for CYP3A by clinical studies and physiologically-based pharmacokinetic model
Authors: Shimizu Ryosuke , Horiuchi Kana , Koshimichi Hiroki , Matsuzaki Takanobu , Yoshida Shinpei , Sakamoto Shingo , Kubota Ryuji 
Published: December 2022

Abstract

Background
Ensitrelvir is a new drug candidate to treat COVID-19 disease. According to the in vitro drug-drug interaction (DDI) study, time-dependent inhibition by ensitrelvir was observed on cytochrome P450 3A (CYP3A). The purpose of this study was to evaluate the effect of ensitrelvir on the pharmacokinetics (PK) of CYP3A substrates by clinial DDI studies and physiologically-based pharmacokinetic (PBPK) analyses.

Methods
Clinical studies: The effect of once daily multiple-doses of ensitrelvir with the loading dose on Day 1/ maintenance dose (750/250 mg) for 6 days on the PK of midazolam (MDZ) was assessed. MDZ was administered on Days -2 and 6. The effects of once daily multiple-doses of ensitrelvir with 750/250 mg for 5 days on the PK of dexamethasone (DXS) and prednisolone (PLS) were also assessed because these corticosteroids were also CYP3A substrates. DXS and PLS were administered on Days -2, 5 (co-administration with ensitrelvir), 9 and 14 to evaluate the effects after the last dose of ensitrelvir.
PBPK analyses: The effects of once daily multiple-doses of ensitrelvir with another dose regimen (the loading dose/mentenance dose [375/125 mg] for 5 days) on the PK of CYP3A substrates were predicted using Simcyp PBPK Simulator (Version 20, Certara UK Limited, UK).

Results
The AUC0-inf of MDZ co-administered with ensitrelvir was increased by 8.80-fold compared to those of MDZ alone, indicating that ensitrelvir is a strong CYP3A inhibitor with 750/250 mg for 6 days. The AUC0-inf of DXS on Day 5 was increased 3.47-fold and the effect of ensitrelvir on the PK of DXS was diminished over time after the last dose of ensitrelvir. The AUC0-inf of PLS on Day 5 was increased 1.25-fold and no clinically meaningful effect of ensitrelvir on the PK of PLS was observed. The PBPK analyses predicted that the co-administration of ensitrelvir increased the AUC of MDZ by 3.83-fold and the AUC of DXS by 2.49-fold following ensitrelvir at 375/125 mg for 5 days. A clinical study with MDZ under the analyses conditions is underway to confirm the PBPK results.

Conclusion
The clinical study revealed that ensitrelvir affects the PK of CYP3A substrates with 750/250 mg for 5 or 6 days. The PBPK analyses suggests that ensitrelvir is expected to a moderate inhibitor of CYP3A with 375/125 mg for 5 days.

Disclosures
Ryosuke Shimizu, Shionogi & Co., Ltd.: employee Kana Horiuchi, Shionogi & Co., Ltd.: employee Hiroki Koshimichi, n/a, Shionogi & Co., Ltd.: employee Takanobu Matsuzaki, Ph.D., Shionogi & Co., Ltd.: Employee Shinpei Yoshida, Ph.D., Shionogi & Co., Ltd.: employee Shingo Sakamoto, n/a, Shionogi & Co., Ltd.: employee Ryuji Kubota, Ph.D., Shionogi & Co., Ltd.: employee|Shionogi & Co., Ltd.: employee.
1136. No Change of Pharmacokinetics of Metformin by Concomitant Use of Ensitrelvir
Authors: Horiuchi Kana , Koshimichi Hiroki , Matsuzaki Takanobu , Shimizu Ryosuke , Yoshida Shinpei , Kubota Ryuji , Sakamoto Shingo 
Published: December 2022

Abstract

Background
Ensitrelvir is a novel oral SARS-CoV-2 3C-like protease inhibitor, and under late clinical development stage for COVID-19 diseases. Ensitrelvir exhibited an inhibition potency for organic cation transporter 1 (OCT1) and multidrug and toxin extrusion protein 1 (MATE1) in in vitro study and clinical drug-drug interaction (DDI) study is required judging from DDI guidance. Metformin is widely used for treatment of diabetes, and is a sensitive substrate for OCT1 and MATE1. We evaluated the effect of ensitrelvir on the pharmacokinetics (PK) of metformin with physiologically-based pharmacokinetic (PBPK) modeling and simulation and clinical DDI study.

Methods
The PBPK model of ensitrelvir was developed based on the physicochemical parameters, in vitro transporter inhibition parameters, and estimated PK parameters for human. DDI simulations between ensitrelvir and metformin were performed. Simcyp PBPK Simulator (Version 20, Certara UK Limited, UK) was used to develop PBPK model and simulate the DDIs. The in vitro 50% inhibitory concentration (IC50) values of each transporter were used as inhibition constant (Ki) for DDI simulations. Based on the PBPK analysis, the clinical DDI study planed.

Results
PBPK analysis: As the result of DDI simulation, ensitrelvir increased the area under the curve (AUC) of metformin by 12%. The result suggests that in vivo DDI potency of ensitrelvir via inhibition of OCT1 or MATE1 would be low at a single dose of ensitrelvir 1000 mg.
Clinical DDI study: The plasma concentration-time profile of metformin and ensitrelvir were monitored after 96 hours from a single dose of metformin with or without ensitrelvir. Ensitrelvir does not have effect on the PK of metformin (a geometric mean of AUC ratio was 1.02, Japanese healthy subjects, N=14), suggesting no MATE1 and OCT1 inhibition by ensitrelvir at a clinical dose. The PBPK analysis could well predict the clinical DDI study result.

Conclusion
The results of PBPK analysis and the clinical DDI study suggest that no OCT1 and MATE1 inhibition by ensitrelvir is in the clinical dose. Therefore, ensitrelvir does not have a clinically meaningful effect on the pharmacokinetic profile of OCT1 and/or MATE1 substrates including metformin.

Disclosures
Kana Horiuchi, Shionogi & Co., Ltd.: employee Hiroki Koshimichi, n/a, Shionogi & Co., Ltd.: employee Takanobu Matsuzaki, Ph.D., Shionogi & Co., Ltd.: Employee Ryosuke Shimizu, Shionogi & Co., Ltd.: employee Shinpei Yoshida, Ph.D., Shionogi & Co., Ltd.: employee Ryuji Kubota, Ph.D., Shionogi & Co., Ltd.: employee|Shionogi & Co., Ltd.: employee Shingo Sakamoto, n/a, Shionogi & Co., Ltd.: employee.
1138. Optimal Duration of Systemic Corticosteroids Use in COVID-19 Treatment: A Meta-analysis
Authors: Yu Nyein , Ssentongo Paddy , Ingram David , Paules Catharine I 
Published: December 2022

Abstract

Background
Corticosteroids confer a survival benefit in hospitalized COVID-19 patients requiring oxygen, but optimal treatment duration remains uncertain. The goal of this meta-analysis is to determine the optimal duration of corticosteroids in the treatment of severe COVID-19. Figure:The effect of systemic steroids on mortality stratified by the duration of treatment in days.
The greatest survival benefit was observed for the treatment duration of up to 6 days (A). No survival benefit was observed beyond 7 days of treatment (B).

Methods
Electronic databases (MEDLINE, Scopus, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, the World Health Organization Global Literature on Coronavirus Disease, CoronaCentral, and Web of Science) and trial registries were searched to March 9, 2022, for randomized controlled trials and observational cohort studies reporting corticosteroid versus no corticosteroid treatment in hospitalized COVID-19 patients. Risk of bias was assessed using the Cochrane Risk of Bias tool (randomized controlled trials) or the Newcastle-Ottawa Scale (observational studies). We estimated the effect of corticosteroids on mortality by random-effects meta-analyses using the generic inverse variance method. Subgroup analyses and meta-analyses were conducted to assess the optimal duration of corticosteroid treatment.

Results
We identified 28 eligible studies consisting of 13,404 hospitalized COVID-19 patients. Median age was 62 years (interquartile range: 59 – 67), and 65% were male. Eight randomized controlled trials and 20 observational studies were included in the meta-analysis of mortality, which suggested a protective association with corticosteroid therapy (risk ratio, 0.75; 95% CI: 0.64; 0.87). Pooled analysis of 19 studies showed the greatest survival benefit for a treatment duration up to 6 days (risk ratio, 0.54; 95% CI, 0.39; 0.74). Survival benefit was 0.68 (95% CI, 0.57; 0.82) up to 7 days, and no survival benefit was observed beyond 7 days of treatment (risk ratio, 0.71; 95% C: 0.51; 1.01).

Conclusion
In this meta-analysis, the optimal duration of corticosteroid treatment for hospitalized COVID-19 patients was up to 6 days, with no additional survival benefit with &gt; 7 days of treatment. Future analyses should stratify survival benefit by baseline disease severity to see if subgroups of patients derive greater benefit from longer courses of steroids.

Disclosures
All Authors: No reported disclosures.
1140. Outcomes and Complications of Tocilizumab and Baricitinib use in Transplant Patients with COVID-19
Authors: Mendoza Maria A , Razonable Raymund R , Abu Saleh Omar M 
Published: December 2022

Abstract

Background
Immunomodulators have been shown to improve the outcomes of patients with severe COVID-19. However, it is not known if tocilizumab or baricitinib use would be beneficial in transplant patients who are already receiving immunomodulating agents. Moreover, augmented immunomodulation may increase risk of opportunistic infection. There are few studies analyzing the outcomes and complications of these medications in this population.

Methods
This is a detailed review of the medical records of all transplant patients who received tocilizumab or baricitinib for COVID-19 indication at our multi-state transplant center from April 2020 to March 2022.

Results
A total of 57 transplant patients received tocilizumab (n=48) or baricitinib (n=9) for management of COVID-19. Baseline characteristics are in Table 1. 60% had received at least one dose of COVID-19 vaccine. At diagnosis, all patients were lymphopenic (median 0.4 x109 cells/L) with high CRP (median 76.8mg/L) and elevated IL-6 levels (median 145.5pg/ml.). The majority had reduction in transplant immunosuppression (75%) and received remdesivir (86%) and dexamethasone (90%). Majority were admitted to the ICU (68%), including 40% who required invasive mechanical ventilation (Table 2). Almost a third developed bacterial or fungal superinfection. Bacterial infections include respiratory cultures with Klebsiella spp, MRSA, P. aeruginosa, Enterobacter spp and Stenotrophomonas. Blood cultures were positive for Klebsiella spp, MDR P. aeruginosa, E faecalis. Fungal infections include three patients with Aspergillus spp infections who received antifungals. No statistical difference was seen in mortality between patients with infections and not infections group. No statistical difference was seen between type of transplants for infection or mortality. Mortality at 90 days was 46%.

Conclusion
Transplant patients who received tocilizumab or baricitinib for severe or critical COVID-19 have poor outcome. This case series found high rates of mortality and opportunistic superinfections after tocilizumab and baricitinib use compared to the current literature. Future directions include a matched case-control study to compare the outcomes in this population.

Disclosures
Raymund R. Razonable, MD, Gilead: Grant/Research Support|Glaxo Smith Kline: Advisor/Consultant|Novartis: DSMB|Regeneron: Grant/Research Support|Roche: Grant/Research Support.
1147. Regional Trends in Favipiravir and Steroid Use in the Treatment of COVID-19
Authors: Asai Yusuke , Tsuzuki Shinya , Matsunaga Nobuaki , Ohmagari Norio 
Published: December 2022

Abstract

Background
Two years have passed since the global outbreak of COVID-19 began. Vaccines and many therapeutic agents have now been developed, and treatment is being conducted in accordance with guidelines. In general, it takes a long time for guidelines to be established, as a large amount of clinical data is required. Therefore, in the early and middle stages of an epidemic, treatment is often based on experience at individual centers. This study focuses on two drugs, Favipiravir and Steroid, and investigates how trends in drug use changed in different regions.

Methods
We compared the proportion of drug administered patients in the COVID-19 Registry Japan (COVIREGI-JP). Data from four COVID-19 epidemic waves, from January 2020 to June 2021, were included for the analysis. To compare regional trends, 10 categories were used based on existing classifications. In addition, Tokyo and Osaka were accounted for separately, for a total of 12 regions. Severity of each case was divided into mild, moderate 1, moderate 2 and severe based on the condition on admission, and the proportion of Favipiravir or Steroid administered cases was calculated for moderate 2 and severe cases.

Results
Favipiravir was administered to more than 50-100% of patients in the first wave. Thereafter, it declined nationwide, with sharp falls in Tokyo (34.9%, 16.5% and 4.3%) and Osaka (48.8%, 41.8% and 8.0%). In Hokkaido, on the other hand, 82.4%, 53.7% and 59.8% of the cases still continued to receive Favipiravir.
In the first wave, Steroid was administered to 20-40% of cases. The proportion gradually increased, with 50-80% in the second wave, and 85.5% in Tokyo, 93.4% in Osaka and 90.2% in Hokkaido in the fourth wave, the majority of cases.
Changes over time in the proportions of cases treated with Favipiravir and Steroid in each region.
The top four and middle four panels show the proportion of cases treated with Favipiravir and Steroid, respectively. The lower epi-curve shows the number of COVID-19 cases in Japan.

Conclusion
We confirmed that the more effective treatment was rapidly spreading throughout the country. More information is available in areas with a large number of cases, such as Tokyo and Osaka, and in facilities that see a large number of cases. On the other hand, it may be difficult for smaller facilities or facilities that do not see many COVID-19 cases. Information from registry studies would be useful in making more effective treatments available earlier and more widely. We believe that further use of COVIREGI-JP would promote standardization of treatment.

Disclosures
All Authors: No reported disclosures.