ABSTRACT
Background. Thymosin-alpha-1 (T alpha 1) may be a treatment option for coronavirus disease 2019 (COVID-19), but efficacy and safety data remain limited. Methods. Prospective, open-label, randomized trial assessing preliminary efficacy and safety of thymalfasin (synthetic form of T alpha 1), compared with the standard of care, among hospitalized patients with hypoxemia and lymphocytopenia due to COVID-19. Results. A total of 49 patients were included in this analysis. Compared with control patients, the incidence of clinical recovery was higher for treated patients with either baseline low-flow oxygen (subdistribution hazard ratio, 1.48 [95% confidence interval, .68-3.25] ) or baseline high-flow oxygen (1.28 [.35-4.63]), although neither difference was significant. Among patients with baseline low-flow oxygen, treated patients, compared with control patients, had an average difference of 3.84 times more CD4(+) T cells on day 5 than on day 1 (P = .01). Nine serious adverse events among treated patients were deemed not related to T alpha 1. Conclusions. T alpha 1 increases CD4(+) T-cell count among patients with baseline low-flow oxygen support faster than the standard of care and may have a role in the management of hospitalized patients with hypoxemia and lymphocytopenia due to COVID-19.
ABSTRACT
Background. Immunocompromised (IC) individuals are at high risk for severe COVID-19, with high morbidity and mortality. CAS+IMD is a monoclonal antibody combination that neutralizes susceptible SARS-CoV-2 variants. We examined the natural history of COVID-19 and the efficacy and safety of CAS+IMD in IC patients (pts) hospitalized with COVID-19. Methods. In a phase 1/2/3 double-blind trial (NCT04426695) conducted Jun 2020 to Apr 2021, prior to the emergence of Omicron-lineage variants, hospitalized COVID-19 pts were randomized 1:1:1 to a single 2.4 g or 8.0 g dose (combined for analyses) of CAS+IMD or placebo (P). Post hoc analyses assessed change in viral load (VL), clinical outcomes (death or mechanical ventilation [MV]), and safety for IC pts with B-cell deficiency or dysfunction (Table 1) vs all pts. Results. 99/1940 (5.1%) treated pts were identified as IC (Table 2). At baseline, IC vs all pts were more likely to be seronegative for SARS-CoV-2 antibodies (68.7% vs 41.2%), and to have higher median VLs (7.21 vs 6.32 log10 copies/mL). Compared to all pts receiving P, IC pts receiving P had slower VL declines. Treatment with CAS +IMD led to a reduction in VL from baseline, with a least-squares mean timeweighted average change in VL difference vs P at Day 7 for IC pts of -0.69 (95% CI: -1.25, -0.41) vs -0.31 (CI: -0.42, -0.20) for all pts;treatment benefit persisted through Day 29 (Fig. 1). Although sample size was small for IC pts, trends in clinical outcomes of death or MV at Day 29 for IC pts (7/64 [11.0%] CAS+IMD vs 6/35 [17.2%] P) were consistent with those in all pts (200/1307 [15.3%] CAS+IMD vs 113/633 [17.9%] P). IC vs all pts treated with CAS+IMD exhibited similar rates of treatment emergent adverse events (TEAEs, 30.4% vs 26.6%), AEs of special interest (grade >=2 hypersensitivity or infusion-related reactions;1.4% vs 2.5%), and death (8.7% vs 12.2%;Table 3). IC and all pts exhibited fewer TEAEs with CAS+IMD vs P. Conclusion. IC vs all pts hospitalized with COVID-19 were more likely to exhibit high VLs at baseline and to be seronegative. In the study, a single dose of CAS+IMD significantly reduced VL in IC pts (for variants circulating at the time, predominantly Alpha) and resulted in fewer events of death or MV. There were no new safety findings in IC pts vs all study pts.
ABSTRACT
Background. Thymosin-alpha-1 (T alpha 1) may be a treatment option for coronavirus disease 2019 (COVID-19), but efficacy and safety data remain limited. Methods. Prospective, open-label, randomized trial assessing preliminary efficacy and safety of thymalfasin (synthetic form of T alpha 1), compared with the standard of care, among hospitalized patients with hypoxemia and lymphocytopenia due to COVID-19. Results. A total of 49 patients were included in this analysis. Compared with control patients, the incidence of clinical recovery was higher for treated patients with either baseline low-flow oxygen (subdistribution hazard ratio, 1.48 [95% confidence interval, .68-3.25] ) or baseline high-flow oxygen (1.28 [.35-4.63]), although neither difference was significant. Among patients with baseline low-flow oxygen, treated patients, compared with control patients, had an average difference of 3.84 times more CD4(+) T cells on day 5 than on day 1 (P = .01). Nine serious adverse events among treated patients were deemed not related to T alpha 1. Conclusions. T alpha 1 increases CD4(+) T-cell count among patients with baseline low-flow oxygen support faster than the standard of care and may have a role in the management of hospitalized patients with hypoxemia and lymphocytopenia due to COVID-19.
ABSTRACT
Background: Tocilizumab is a humanized monoclonal antibody that targets Interleukin-6 receptors. Recent trials have shown that tocilizumab may be effective against COVID-19. It is also known that tocilizumab may be associated with mild aminotransferase elevation, however, there are very limited data on hepatotoxicity of tocilizumab in patients with COVID- 19. Here we report our institutional experience on the development of liver injury after tocilizumab use in hospitalized patients with COVID-19. Methods: We analyzed all consecutive adult hospitalized patients who had PCR confirmed COVID-19 and were admitted to our hospital network between January 1st, 2021, and November 15th, 2021. To be considered eligible for inclusion patients should had an admission liver injury panel and at least one additional follow-up panel before discharge. Patients with baseline alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >5 times of the upper normal limit were excluded. Liver injury was measured by ALT, AST, or total bilirubin elevation. Grading was based on the Common Terminology Criteria for Adverse Events version 5.0. The primary outcome of interest was to estimate the incidence of liver injury among patients who received tocilizumab. As a secondary outcome, we examined the association of all-grade liver injury with tocilizumab use by utilizing a multivariate logistic regression model adjusted for demographics, comorbidities, Remdesivir use, and baseline COVID-19 severity based on the NEWS score. Results: Among 1409 consecutive hospitalized patients who met the inclusion criteria, we identified 87 patients who received tocilizumab. Baseline patient characteristics are depicted on Table 1. We found that the incidence of any grade AST elevation was higher in the tocilizumab versus non-tocilizumab group (24.1% vs 13%;p=0.015), with similar findings in ALT (32.1% vs 18%;p=0.016) and bilirubin (18% vs 4.5% p<0.001) (Table 2). Likewise, in our multivariate logistic regression model, patients who received tocilizumab were more likely to have had elevated ALT (OR 2.16;95% CI: 1.31-3.55), AST (OR 2.56;95% CI: 1.48-4.43), or bilirubin (OR 3.30;95% CI: 1.57-6.92), compared to those who did not receive the drug. Conclusion: While tocilizumab is frequently utilized in the treatment of COVID-19 patients, few studies have evaluated its hepatotoxic potential in this population. Based on our institutional experience, tocilizumab use in hospitalized patients with COVID-19 is associated with ALT, AST, and bilirubin elevation even after adjusting for COVID-19 severity. However, the majority of hepatic injury events were graded as level I (mild injury) and severe hepatotoxicity was rare. Further studies are needed to confirm these findings, while monitoring of hepatic function after tocilizumab use is warranted, especially in patients with chronic liver disease. (Table Presented)
ABSTRACT
Background. Casirivimab and imdevimab (CAS/IMDEV) is authorized for emergency use in the US for outpatients with COVID-19. We present results from patient cohorts receiving low flow or no supplemental oxygen at baseline from a phase 1/2/3, randomized, double-blinded, placebo (PBO)-controlled trial of CAS/IMDEV in hospitalized patients (pts) with COVID-19. Methods. Hospitalized COVID-19 pts were randomized 1:1:1 to 2.4 g or 8.0 g of IV CAS/IMDEV (co-administered) or PBO. Primary endpoints were time-weighted average (TWA) change in viral load from baseline (Day 1) to Day 7;proportion of pts who died or went on mechanical ventilation (MV) through Day 29. Safety was evaluated through Day 57. The study was terminated early due to low enrollment (no safety concerns). Results. Analysis was performed in pooled cohorts (low flow or no supplemental oxygen) as well as combined treatment doses (2.4 g and 8.0 g). The prespecified primary virologic analysis was in seronegative (seroneg) pts (combined dose group n=360;PBO n=160), where treatment with CAS/IMDEV led to a significant reduction in viral load from Day 1-7 (TWA change: LS mean (SE): -0.28 (0.12);95% CI: -0.51, -0.05;P=0.0172;Fig. 1). The primary clinical analysis had a strong positive trend, though it did not reach statistical significance (P=0.2048), and 4/6 clinical endpoints prespecified for hypothesis testing were nominally significant (Table 1). In seroneg pts, there was a 47.0% relative risk reduction (RRR) in the proportion of pts who died or went on MV from Day 1-29 (10.3% treated vs 19.4% PBO;nominal P=0.0061;Fig. 2). There was a 55.6% (6.7% treated vs 15.0% PBO;nominal P=0.0032) and 35.9% (7.3% treated vs 11.5% PBO;nominal P=0.0178) RRR in the prespecified secondary endpoint of mortality by Day 29 in seroneg pts and the overall population, respectively (Fig. 2). No harm was seen in seropositive patients, and no safety events of concern were identified. Conclusion. Co-administration of CAS/IMDEV led to a significant reduction in viral load in hospitalized, seroneg pts requiring low flow or no supplemental oxygen. In seroneg pts and the overall population, treatment also demonstrated clinically meaningful, nominally significant reductions in 28-day mortality and proportion of pts dying or requiring MV.
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Background: Remdesivir (RDV) (GS-5734) is a nucleotide analog prodrug that can inhibit RNA polymerases of SARSCoV-2. RDV received Emergency Use Authorization (EUA) on May 1, 2020 and FDA approval on October 22, 2020. Although RDV use has been associated with hepatotoxicity, evidence remains limited. Here we report our institute's experience after a year of RDV use in hospitalized patients with COVID-19. Methods: We analyzed all consecutive adult hospitalized patients with a primary diagnosis of COVID-19 who were admitted to our hospital network between May 1st 2020 and May 1st, 2021. Patients who had RT- PCR confirmed COVID-19, had an admission liver injury panel and at least an additional follow-up panel before discharge were considered eligible for inclusion. Patients with baseline ALT or AST >5 times of the upper normal limit were excluded, as they were not eligible for RDV (institutional guidelines). Liver injury was measured by ALT, AST or total bilirubin elevation and was graded based on the Common Terminology Criteria for Adverse Events version 5.0. The primary outcome of interest was to estimate the incidence of liver injury among patients who received RDV. As a secondary outcome we examined the association of liver injury with RDV use by utilizing a multivariate logistic regression model adjusted for age, sex, race, comorbidities, and baseline COVID-19 severity based on the NEWS score. Results: We identified 2,380 consecutive hospitalized patients who met the above-mentioned criteria. Among these patients, 1,260 (52.9%) received RDV. Baseline characteristics are depicted on Table 1a. We found that any grade ALT elevation was more common in RDV group (18.3%) vs non-RDV (14.2%) (p=0.002). However, AST and bilirubin elevation, as well as the incidence of severe liver injury (≥ Grade 3 in any of AST, ALT, or bilirubin) were similar in the RDV and non-RDV group (Table 1b). In our multivariate logistic regression model, patients with ALT elevation were more likely to have had received RDV (OR 1.27;95% CI: 1.01-1.60). Exposure to RDV was not associated with AST or total bilirubin elevation. Conclusion: To the best of our knowledge this is the largest cohort to date assessing the hepatotoxic effect of RDV on patients with COVID-19. Among hospitalized patients with COVID-19, RDV use is associated with ALT elevation but not with AST or bilirubin elevation. RDV-associated hepatotoxicity is rare but monitoring of liver enzymes, and especially ALT, during RDV treatment is warranted.
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AIM: To determine the overall rate of chest imaging findings in asymptomatic cases, describe the most common patterns found, and determine the rate of later symptom development in these initially asymptomatic cases. MATERIALS AND METHODS: The PubMed and EMBASE databases were searched until 1 May 2020, for studies examining the proportion of positive chest imaging findings in asymptomatic cases diagnosed with COVID-19 and a random-effects meta-analysis of proportions was performed. Heterogeneity was assessed using the I2 statistic. RESULTS: Among 858 non-duplicate studies, seven studies with a total of 231 asymptomatic cases met the inclusion criteria. In the primary analysis, the pooled estimate of the overall rate of positive chest computed tomography (CT) findings among asymptomatic cases was 63% (95% confidence interval [CI]: 44-78%). Among 155/231 cases that were followed up for later symptom development, 90/155 remained asymptomatic and 65/155 developed symptoms during the study period (that ranged between seven and 30 days of follow-up). The pooled estimate of the rate of positive chest CT findings was 62% (95% CI: 38-81%) in cases that remained asymptomatic, while it was 90% (95% CI: 49-99%) in cases that developed symptoms. Among CT findings, the pooled estimate of the overall rate of ground-glass opacities (GGO) at CT alone was 71% (95% CI: 50-86%). Among other CT findings reported, 22/231 patients had GGO with consolidation, 7/231 patients had stripe shadows with or without GGO, and 8/231 patients had GGO with interlobular septal thickening. Among initially asymptomatic cases with positive CT findings, the pooled estimate of the overall rate of later symptom development was 26% (95% CI: 14-43%). CONCLUSION: In COVID-19, asymptomatic cases can have positive chest CT findings, and COVID-19 should be considered among cases with CT abnormalities even when there are no other symptoms. There is a need for close clinical monitoring of asymptomatic cases with radiographic findings as a significant percentage will develop symptoms.