Infectious Diseases and Therapy

BackgroundThe proportion of critically ill COVID-19 patients has collapsed hospital care worldwide. The need for alternative therapies for this group of patients is imperative. This study aims to compare the safety and efficacy of convalescent plasma (CP) compared with human immunoglobulin (IVIg) in patients requiring the administration of high oxygen levels or mechanical ventilation. MethodsThis is a controlled, randomized, open clinical trial of patients with pneumonia secondary to SARS-CoV-2 infection, that fulfilled criteria for severe or critical disease. They were randomized in a 1:2 ratio; group 1 was administered IVIg at a dose of 0.3 grams per kilogram of ideal weight, in an 8-hour infusion every 24 hours, for 5 days. Group 2 was administered 200 ml of CP infused in 2 hours, for 2 days. The primary outcomes were duration of hospitalization and mortality at 28 days. ResultsOne hundred and ninety (190) patients were randomized; 130 to the CP group, and 60 to the IVIg group. Their average age was 58 years (IQR 47 - 72), and most were male (n= 119, 62.6 %). On inclusion, 85.2 % of patients (n=162) were on invasive mechanical ventilation therapy. Overall mortality in all included patients was 53 % (n= 102), with a median follow-up of 14 days (IQI 8 - 26). Mortality at 28 days was 45.2 % (n=86). In the intention-to-treat analysis, there was no difference between groups neither in mortality on follow-up (53.8 vs. 53.3, p =1.0) nor at 28 days (46.2 vs 43 %, p=0.75, Log Rank p = 0.83). Per-protocol analysis between treatment groups revealed no difference in mortality throughout hospitalization (51.5 vs 51.4 %, p=1.0) nor after 28 days (42.1 vs 42.87 %, p=0.92 Log Rank p = 0.54). Only 23 patients in the CP group received plasma with detectable anti-SARS-CoV-2 antibodies. ConclusionsIn critically ill patients or on invasive mechanical ventilation for treatment of Covid-19, the use of CP is not superior to IVIg in terms of hospitalization duration or mortality. The use of CP is based on complex logistics and requires an assured level of antibodies if used therapeutically. IVIg does not appear to be useful in this group of patients. clinicaltrials.gov identifier: NCT04381858.

BackgroundStaphylococcus aureus bloodstream infection (SAB) is treated with at least 14 days of intravenously administered antimicrobials. We assessed the efficacy and safety of an early oral switch therapy in patients at low risk for SAB-related complications. MethodsIn an international non-inferiority trial, we randomized patients with SAB after 5 to 7 days of intravenous antimicrobial therapy to either switch to an oral antimicrobial or to continue with intravenous standard therapy. Main exclusion criteria were signs and symptoms of complicated SAB, non-removable foreign devices, and severe comorbidity. Composite primary endpoint was the occurrence of any SAB-related complication (relapsing SAB, deep-seated infection, and mortality attributable to SAB) within 90 days. Results213 patients were randomized into the intention-to-treat population. In the oral switch group, 14/108 (13%) participants reached the primary endpoint versus 13/105 (12%) in the standard therapy group (adjusted difference 0.7%, 95% confidence interval [CI] -7.8% to 9.1%). Participants in the oral switch group were discharged earlier (median hospital stay from SAB onset of 12 days versus 16 days; adjusted difference -3.1 days [95% CI -7.5 to 1.4]). There was no statistical difference in 30-day survival and complications of intravenous administration. More participants in the oral group experienced at least one serious adverse event (34% versus 26%, p=0.292). ConclusionOral switch was non-inferior to intravenous standard therapy in participants with low-risk SAB. However, a careful assessment of patients for signs and symptoms of complicated SAB at time of presentation and thereafter is necessary before considering early oral switch therapy. The trial was registered as NCT01792804 in ClinicalTrials.gov, as DRKS00004741 in the German Clinical trials register, and as EudraCT 2013-000577-77.

ImportanceRecent changes in the Infectious Diseases and Healthcare Epidemiology Societies of America (IDSA-SHEA) guidelines for managing Clostridioides difficile infections (CDI) have placed fidaxomicin as first-line treatment. ObjectiveTo estimate the net cost of first line fidaxomicin compared to vancomycin in the American and Canadian healthcare systems and to estimate the price points at which fidaxomicin would become cost saving. In Canada, net costs were from the public payer perspective. In the US, costs were from a healthcare and payer perspective. Data sourcesWe identified all randomized controlled trials comparing fidaxomicin with vancomycin through the 2021 IDSA-SHEA guideline update. Medication costs were obtained from internet prices (US) and the Quebec drug formulary (Canada). The average cost of a CDI recurrence was established through a systematic review for each country. Study selectionFor fidaxomicin efficacy, we included double-blind and placebo-controlled trials. For the systematic review of recurrence costs, studies were included if they were primary research articles, had a cost-analysis of CDI, included cases of recurrent CDI, and were calculated with cost parameters from American or Canadian healthcare systems. Studies were excluded if the population was solely pediatric or hospitalized. Data extraction and SynthesisFor the efficacy meta-analysis, data was pooled using a restricted maximal likelihood random effects model. For the cost review, the mean cost across identified studies was adjusted to reflect July 2022 dollars. Main Outcomes and MeasuresThe primary outcome of the meta-analysis was CDI recurrence at Day 40. The primary outcome of the systematic review was the average cost of a CDI recurrence in the American and Canadian healthcare systems. The objective was to estimate the net cost per recurrence prevented and the price point below which fidaxomicin would be cost saving to either the public payer (Canada) or the insurer (US). ResultsThe estimated mean system cost of a CDI recurrence was $15147USD and $8806CAD, respectively. At current drug pricing, to prevent one recurrence by using first line fidaxomicin over vancomycin would cost $43904USD (95%CI $35123-$65856) and $13,760CAD (95%CI $11,008-$20,640), respectively. The likelihood of fidaxomicin offering cost savings varies by country, with a 95% probability of fidaxomicin being cost saving if priced below $1180USD or $860CAD respectively. Conclusions and RelevanceAn increased drug expenditure on fidaxomicin will not be offset through recurrence prevention unless the fidaxomicin price is negotiated.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron subvariants are expected to be resistant to Bebtelovimab (BEB) monoclonal antibody (MAb) and the real-world experience regarding its effectiveness is scarce. This retrospective cohort study reports a data analysis in Banner Healthcare System (a large not-for-profit organization) between 4/5/2022 and 8/1/2022 and included 19,778 Coronavirus disease-19 (COVID-19) positive (by PCR or direct antigen testing) patients who were selected from Cerner-Electronic Health Record after the exclusions criteria were met. The study index date for cohort was determined as the date of BEB MAb administration or the date of the first positive COVID-19 testing. The cohort consist of COVID-19 infected patients who received BEB MAb (N=1,091) compared to propensity score (PS) matched control (N=1,091). The primary outcome was the incidence of 30-day all-cause hospitalization and/or mortality. All statistical analyses were conducted on the paired (matched) dataset. For the primary outcome, the event counts and percentages were reported. Ninety-five percent Clopper-Pearson confidence intervals for percentages were computed. The study cohorts were 1:1 propensity matched without replacement across 26 covariates using an optimal matching algorithm that minimizes the sum of absolute pairwise distance across the matched sample after fitting and using logistic regression as the distance function. The pairs were matched exactly on patient vaccination status, BMI group, age group and diabetes status. Compared to the PS matched control group (2.6%; 95% confidence interval [CI]: 1.7%, 3.7%), BEB MAb use (2.2%; 95% CI: 1.4%, 3.3%) did not significantly reduce the incidence of the primary outcome (p=0.67). In the subgroup analysis, we observed similar no-difference trends regarding the primary outcomes for the propensity rematched BEB MAb treated and untreated groups, stratified by patient vaccination status, age (<65 years or [&ge;]65), and immunocompromised status (patients with HIV/AIDS or solid organ transplants or malignancy including lymphoproliferative disorder). The number needed to treat (1/0.026-0.022) with BEB MAb was 250 to avoid one hospitalization and/or death over 30 days. The BEB MAb use lacked efficacy in patients with SARS-CoV-2 Omicron subvariants (mainly BA.2, BA.2.12.1, and BA.5) in the Banner Healthcare System in the Southwestern United States.

Current guidelines prioritize the use of the Azvudine in coronavirus disease 2019 (COVID-19) patients. However, the clinical effectiveness of Azvudine in real-world studies was lacking, despite the clinical trials showed shorter time of nucleic acid negative conversion. To evaluate the clinical effectiveness following Azvudine treatment in hospitalized COVID-19 patients, we identified 1505 hospitalized COVID-19 patients during the study period, with a follow-up of up to 29 days. After exclusions and propensity score matching, we included 226 Azvudine recipients and 226 matched controls. The lower crude incidence rate of composite disease progression outcome (4.21 vs. 10.39 per 1000 person-days, P=0.041) and all-cause mortality (1.57 vs. 6.00 per 1000 person-days, P=0.027) were observed among Azvudine recipients compared with matched controls. The incidence rates of initiation of invasive mechanical ventilation were also statistically different between the groups according to the log-rank tests (P=0.020). Azvudine treatment was associated with significantly lower risks of composite disease progression outcome (hazard ratio [HR]: 0.43; 95% confidence interval [CI]: 0.18 to 0.99) and all-cause death (HR: 0.26; 95% CI: 0.07 to 0.94) compared with matched controls. Subgroup analyses indicated robustness of the point estimates of HRs (ranged from 0.14 to 0.84). Notably, male Azvudine recipients had a stronger effectiveness than female recipients with respect to both composite outcome and all-cause death. These findings suggest that Azvudine treatment showed substantial clinical benefits in hospitalized COVID-19 patients, and should be considered for use in this population of patients.

BackgroundThe use of convalescent plasma (CP) to treat COVID-19 has shown promising results; however, its effectiveness remains uncertain. The purpose of this study was to determine the safety and mortality of CP among patients hospitalized with COVID-19. Study Design and MethodsThis multicenter, open-label, uncontrolled clinical trial is currently being conducted at nine hospitals in Chile. Patients hospitalized due to COVID-19 who were still within 14 days since symptom onset were classified into four groups: Patients with cancer and severe COVID-19. Patients with cancer and non-severe COVID-19. Patients with severe COVID-19 and patients with non-severe COVID-19 only. The intervention involved two 200-cc. CP transfusions with anti-SARS-CoV-2 IgG titers [&ge;] 1:320 collected from COVID-19-recovered donors. Results192 patients hospitalized for COVID-19 received CP transfusions. At the first transfusion, 90.6% fulfilled the criteria for severity, and 41.1% required mechanical ventilation. 11.5% of the patients had cancer. Overall 7-day and 30-day mortality since the first CP transfusion was 5.7% and 16.1% respectively. There were no differences at either time point in mortality between the four groups. Patients on mechanical ventilation when receiving CP had higher mortality rates than those who were not (22.8% vs. 11.5%; p = 0.037). Overall 30-day mortality was higher in patients over 65 than in younger patients (p = 0.019). Severe adverse events were reported in four patients (2.1%) with an overall transfusion-related lung injury rate of 1.56%. No CP-related deaths occurred. DiscussionCP is safe when used in patients with COVID-19 even when also presenting severity criteria or risk factors. Our mortality rate is comparable to reports from larger studies. Controlled clinical trials are required to determine efficacy. RegistrationNCT04384588

Background and aimsImmunocompromised patients have a reduced ability to generate antibodies after COVID-19 vaccination and are at higher risk of SARS-CoV-2 infection, complications and mortality. Tixagevimab/Cilgavimab (Evusheld) is a monoclonal antibody combination which bind to the SARS-CoV-2 spike protein, preventing the virus entering human cells. The phase III PROVENT trial reported that immunocompromised patients given Tixagevimab/Cilgavimab had a significantly reduced risk of COVID-19 infection. However, PROVENT was conducted before the SARS-CoV-2 Omicron became prevalent. This systematic review provides an updated summary of real-world clinical evidence of Tixagevimab/Cilgavimab effectiveness in immunocompromised patients. MethodsTwo independent reviewers conducted PubMed and medRxiv searches for the period of 01/01/2021 to 01/10/2022. Clinical studies which reported the primary outcome of breakthrough COVID-19 infections after Tixagevimab/Cilgavimab administration were included in the review. COVID-19-related hospitalisations, ITU admissions and mortality were assessed as secondary outcomes. Clinical effectiveness was determined using the case-control clinical effectiveness methodology. The GRADE tool was used to ascertain the level of certainty for the primary outcome in each study. Results17 clinical studies were included, comprising 24,773 immunocompromised participants of whom 10,775 received Tixagevimab/Cilgavimab. Most studies reported clinical outcomes during the SARS-CoV-2 Omicron wave. Six studies compared a Tixagevimab/Cilgavimab intervention group to a control group. Overall, the clinical effectiveness of prophylactic Tixagevimab/Cilgavimab against COVID-19 breakthrough infection, hospitalisation and ITU admission were 40.47%, 69.23% and 87.89%, respectively. For prevention of all-cause and COVID-19-specifc mortality, overall clinical effectiveness was 81.29% and 86.36%, respectively. ConclusionsThere is a growing body of real-world evidence validating the original PROVENT phase III study regarding the clinical effectiveness of Tixagevimab/Cilgavimab as prophylaxis for immunocompromised patients, notably demonstrating effectiveness during the Omicron wave. This review demonstrates the clinical effectiveness of prophylactic Tixagevimab/Cilgavimab at reducing COVID-19 infection, hospitalisation, ITU admission and mortality for immunosuppressed individuals. It is important that ongoing larger-scale and better-controlled real world studies are initiated and evaluated to provide ongoing certainty of the clinical benefit of prophylactic antibody treatment for immunocompromised patients in the face of new variants.

BackgroundCOVID-19 convalescent plasma (CCP) is obtained from people recently recovered from COVID-19 and contains viral-neutralizing antibodies. Because such treatment is safe and effective against SARS-CoV-2, the US Food and Drug Administration (FDA) has recently authorized the use of CCP for COVID-19 patients with immunodeficiencies. Currently available CCP is a "hybrid" product with antibodies from individuals who had both infection and vaccination (vaccine-boosted CCP). In this context, there is growing interest in CCP treatment outcomes in specific groups of immunocompromised patients. Specifically, B-cell depleted patients are at risk of not producing antibodies after either infection or vaccination. Hence, B-cell depleted patients are conceivably among those who would benefit the most from CCP. We thus conducted a systematic review and individual patient data meta-analysis to assess characteristics associated with 60-day survival in B-cell depleted patients transfused with CCP. MethodsThe last search was April 2nd, 2024, and included all studies using CCP in B-cell depleted patients. Whenever not available in the publication, we requested individual participant data from corresponding authors of eligible studies. Risk of bias was assessed using Joanna Briggs Institute Critical Appraisal Tools. Data were analyzed using conditional logistic regression. ResultsWe describe individual patient data extracted from 85 studies and synthesized into a cohort of 570 patients. The overall 60-day survival rate was 86.5%. Of patients with information available, 70.1% achieved SARS-CoV-2 clearance, and 64.3% had clinical improvement within 5 days of CCP transfusion. After controlling for age, sex, calendar year of infection and World Health Organization (WHO) disease severity, we found a significant association between 60-day survival and days since last anti-CD20 dose (OR=1.16 per 10-day increase; 95% CI 1.04 to 1.29; p=0.007) and transfusion of vaccine-boosted CCP (OR=9.49; 95% CI 2.01 to 44.82; p=0.005), but not with concomitant remdesivir treatment (OR=1.31; 95% CI 0.66 to 2.61; p=0.440). DiscussionOur study is limited to individual participant data analysis, with a majority of the studies included being case series and case reports. Overall survival in our cohort of B-cell depleted patients was consistent with prior meta-analysis of randomized controlled trials on survival of immunocompromised patient transfused with CCP ([~]84%). A novel finding from this analysis is that vaccine-boosted CCP with a presumably higher content of neutralizing antibodies is associated with a high survival benefit. RegistrationThe protocol for this systematic review and individual participant data meta-analysis was registered with PROSPERO (CRD42024516513) on March 1st, 2024.

ObjectivesEfficacy of convalescent plasma in COVID-19 pneumonia (CPP) is uncertain, especially in immunocompromised patients. CORIMUNO-CORIPLASM is an open-label, Bayesian randomised clinical trial embedded in the CORIMUNO trials platform that evaluated the efficacy of CCP in patients with moderate COVID-19. Setting19 university and general hospitals across France. ParticipantsAdult hospitalized with a positive SARS-CoV2 test, duration of symptoms < 9 days and WHO score severity 4 or 5 who signed written inform consent. InterventionOpen label randomisation to either usual care (UC) or 4 units (200-220 ml/unit, 2 units/day over 2 consecutive days) of convalescent plasma (CCP) with a seroneutralisation titer > 40. OutcomesPrimary outcome was proportion of patients with a WHO-Clinical Progression Score (CPS) [&ge;]6 on the 10-point scale on day (d) 4 (higher values indicating a worse outcome) and survival without ventilation or additional immunomodulatory treatment by day 14. Secondary outcomes included evolution of WHO-CPS, overall survival, time to discharge and time to oxygen supply independency. Pre-defined subgroups analyses included immunosuppression status, duration of symptoms before randomization and use of steroids. ResultsA total of 120 patients were recruited and assigned to CCP (n=60) or UC (n=60), including 22 (CCP) and 27 (UC) immunocompromised patients. Thirteen (22%) patients with CCP had a WHO-CPS [&ge;]6 at day 4 versus 8 (13%) with UC, adjusted odds ratio (aOR) 1.88 [95%CrI 0.71 to 5.24]. By day 14, 19 (31.6%) patients with CCP and 20 (33.3%) patients with UC had ventilation, additional immunomodulatory treatment or had died. Cumulative incidence of death was 3 (5%) with CCP and 8 (13%) with UC at day 14 (aHR 0.40 [95%CrI 0{middle dot}10 -1{middle dot}53]), and 7 (12%) with CCP and 12 (20%) with UC at day 28 (aHR 0.51 [95%CrI 0.20-1.32]). I n a s ubgroup analysis performed in immunocompromised patients, the association of CCP with mortality was HR 0.39 [95%CI 0.14-1.10]. ConclusionsCCP did not improve early outcomes in patients with moderate COVID-19. Its efficacy in immunocompromised patients needs to be further explored. Trial registrationclinicaltrials.gov Identifier: NCT04345991 KEY MESSAGES BOXO_ST_ABSWhat is already known on this topic?C_ST_ABSO_LIConvalescent plasma treatment, i.e., passive polyclonal antibody administration to provide immediate immunity, has been used to improve the survival rate of patients with severe acute respiratory syndromes of viral etiology in emergency settings and times where there was no specific antiviral treatment C_LIO_LIAt the early stages of the COVID-19 pandemic, using high titre COVID-19 convalescent plasma (CCP) appeared to be an immediate therapeutic option. C_LIO_LIHowever, a large number of randomised clinical trials and observational studies have yielded conflicting results regarding the efficacy of CCP. C_LIO_LIFurthermore, the efficacy of CCP in patients with underlying immunosuppression has been evaluated only in a limited manner. C_LIO_LIThe emergence of variants resistant to other passive immunotherapy approaches, ie monoclonal antibodies, has limited the therapeutics options for such patients C_LI What this study adds ?O_LIThis multicentre randomised clinical trial provided evidence that high titre CCP in a population hospitalised with a mild to moderate form of COVID-19 within 9 days of symptoms onset may not improve early outcome. C_LIO_LIIn the subgroup of patients with immunosuppression, there was evidence suggesting a lower odds of death 14 and 28 days after CCP transfusion, albeit without reaching significance. C_LI How does this study might affect research, practice of policyO_LIThe result of study, along with the recent data obtained from other trials and cohort studies supports further evaluation of CCP transfusion in patients with underlying immunosuppression for whom therapeutic options are currently scarce if non-existent, due to the ever changing genetic variability of SARS-CoV2. C_LI

OBJECTIVESTo assess the efficacy and safety of convalescent plasma plus standard of care (CP + SoC) compared with standard of care (SoC) alone in patients hospitalized for moderate to severe COVID-19 who do not yet require mechanical ventilation. METHODSPhase 2 randomized, parallel-group, randomized, open-label, controlled, superiority, single-center clinical trial. This clinical trial has been registered in REPEC with the following ID: 013-20. Hospitalized adult patients with moderate to severe COVID-19 were enrolled. The allocation ratio was 1:1 in a variable-size permuted block randomization scheme. The primary outcome was death 28 days after the intervention. Secondary outcomes were mortality at 14 and 56 days, time to death at 56 days, time in the ICU at 28 days, time on a mechanical ventilator at 28 days, frequency of adverse events, and frequency of serious adverse events. RESULTSA total of 64 participants were enrolled, 32 were assigned to CP + SoC, and 32 to SoC. One participant assigned to CP + SoC withdrew his informed consent before applying the treatment. At day 28, there were no statistically significant differences for the primary outcome between the CP + SoC and SoC groups (relative risk: 2.06; 95%CI 0.73 to 7.11; p = 0.190). No differences were found in the incidences of mortality at 56 days (hazard ratio: 2.21; 95%CI 0.66 to 7.33; p = 0.182), admission to the ICU at 28 days (sub-hazard ratio: 2.06; 95%CI 0.57 to 8.55; p = 0.250), admission to mechanical ventilation at 28 days (sub-hazard ratio: 2.19; 95%CI 0.57 to 8.51; p = 0.260). Estimates for days 14 were similar. No infusion-related adverse events were reported during the study. There were no statistically significant differences in the frequency of any adverse events (odds ratio: 2.74; 95%CI 0.90 to 9.10; p = 0.085) or the frequency of serious adverse events (odds ratio: 3.60; 95%CI 0.75 to 26.1; p = 0.75). CONCLUSIONSNo evidence was found that CP had a significant effect in reducing 28-day mortality. There was also no evidence that the frequency of adverse events was higher in those who received CP + SoC than those who received only SoC.

BackgroundIn patients with COVID-19 and baseline soluble urokinase plasminogen receptor plasma (suPAR) levels [&ge;] 6ng/mL, early administration of anakinra, a recombinant interleukin-1 receptor antagonist, may prevent disease progression and death. In case of suPAR testing unavailability, the Severe COvid Prediction Estimate (SCOPE) score may be used as an alternative in guiding treatment decisions. MethodsWe conducted a monocenter, retrospective cohort study, including patients with SARS-CoV2 infection and respiratory failure. Patients treated with anakinra (anakinra group, AG) were compared to two control groups of patients who did not receive anakinra, respectively with [&ge;] 6 ng/mL (CG1) and < 6 ng/mL (CG2) baseline suPAR levels. Controls were paired by age, sex, date of admission and vaccination status. Primary endpoint of the study was disease progression at day 14 from admission, as defined by patient distribution on a simplified version of the 11-point World Health Organization Clinical Progression Scale (WHO-CPS). ResultsBetween July, 2021 and January, 2022, 153 patients were included, among which 56 were treated with off-label anakinra, 49 retrospectively fulfilled prescriptive criteria for anakinra and were assigned to CG1, and 48 presented with suPAR levels < 6ng/mL and were assigned to CG2. At day 14, when comparing to CG1, patients who received anakinra had significantly reduced odds of progressing towards worse clinical outcome both in ordinal regression analysis (OR 0.25, 95% CI 0.11-0.54, p<0.001) and in multivariable analysis (OR 0.19, 95% CI 0.03-0.82, p=0.037), and these results were confirmed even when controlling for age, sex, BMI and vaccinal status. Sensitivities of baseline suPAR and SCOPE score in predicting progression towards severe disease or death at day 14 were similar (83% vs 100%, p=0.59). ConclusionThis real-word, retrospective cohort study confirmed the safety and the efficacy of suPAR-guided, early use of anakinra in hospitalized COVID-19 patients with respiratory failure.

Objective To assess the effectiveness of corticosteroids on outcomes of patients with mild COVID-19 pneumonia. Methods We used routine care data from 51 hospitals in France and Luxembourg to assess the effectiveness of corticosteroids at 0.8 mg/kg/day eq. prednisone (CTC group) vs standard of care (no-CTC group) among patients [&le;] 80 years old with COVID-19 pneumonia requiring oxygen without mechanical ventilation. The primary outcome was intubation or death at Day 28. Baseline characteristics of patients were balanced using propensity score inverse probability of treatment weighting. Results Among the 891 patients included in the analysis, 203 were assigned to the CTC group. At day 28, corticosteroids did not reduce the rate of the primary outcome (wHR 0.92, 95% CI 0.61 to 1.39) nor the cumulative death rate (wHR 1.03, 95% CI 0.54 to 1.98). Corticosteroids significantly reduced the rate of the primary outcome for patients requiring oxygen [&ge;] at 3L/min (wHR 0.50, 95% CI 0.30 to 0.85) or C-Reactive Protein (CRP) [&ge;] 100mg/L (wHR 0.44, 95%CI 0.23 to 0.85). We found a higher number of hyperglycaemia events among patients who received corticosteroids, but number of infections were similar across the two groups. Conclusions We found no association between the use of corticosteroids and intubation or death in the broad population of patients [&le;]80 years old with COVID-19 hospitalized in non-ICU settings. However, the treatment was beneficial for patients with [&ge;] 3L/min oxygen or CRP [&ge;] 100mg/L at baseline. These data support the need to confirm the right timing of corticosteroids for patients with mild COVID.

BackgroundCOVID-19 Convalescent Plasma (CCP) was an early and widely adopted putative therapy for severe COVID-19. Results from randomized control trials and observational studies have failed to demonstrate a clear therapeutic role for CCP for severe SARS-CoV-2 infection. Underlying these inconclusive findings is a broad heterogeneity in the concentrations of neutralizing antibodies (nAb) between different CCP donors. The present study was designed to evaluate nAb titer threshold for clinically effective CCP. MethodsWe conducted a double-blind, phase 2 study to evaluate the safety and effectiveness of nAb titer-defined CCP in adults admitted to an academic referral hospital. Patients positive on a SARS-CoV-2 nucleic acid amplification test and with symptoms for < 10 days were eligible. Participants received either CCP with nAb titers [&ge;]1:160-1:640 (standard titer group) or >1:640 (high titer group) in addition to standard of care treatments. Adverse events were contrasted by CCP titer. The primary clinical outcome was time to hospital discharge, with mortality and respiratory support evaluated as secondary outcomes. FindingsBetween August 28 and December 4, 2020, 316 participants were screened, 55 received CCP, with 41 and 14 receiving standard versus high titer CCP, respectively. Participants were a median of 61 years of age (IQR 52-67), 36% women, 25% Black and 33% Hispanic. Severe adverse events (SAE) ([&ge;] grade 3) occurred in 4 (29%) and 23 (56%) of participants in the high versus standard titer groups, respectively by day 28 (Risk Difference -0.28 [95% CI -0.56, 0.01]). There were no observed treatment-related AEs. By day 55, time to hospital discharge was shorter among participants receiving high versus standard titer, accounting for death as a competing event (hazard ratio 1.94 [95% CI 1.05, 3.58], Grays p=0.02). InterpretationIn this phase 2 trial in a high-risk population of patients admitted for Covid-19, we found earlier time to hospital discharge and lower occurrences of life-threatening SAEs among participants receiving CCP with nAb titers >1:640 compared with participants receiving CCP with lower nAb titer CCP. Though limited by a small study size these findings support further study of high-nAb titer CCP defined as >1:640 in the treatment of COVID-19. FundingThis clinical study was supported by the UNC Health Foundation and the North Carolina Policy Collaboratory at the University of North Carolina at Chapel Hill with funding from the North Carolina Coronavirus Relief Fund established and appropriated by the North Carolina General Assembly. The laboratory assays for neutralizing antibody titers and SARS-CoV-2 specific antibody-binding assays were partially supported by The NIH NCI/NIAID SeroNet Serocenter of Excellence Award U54 CA260543. Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSCOVID-19 Convalescent Plasma (CCP) has emergency use authorization from the FDA for early treatment of COVID-19 in either outpatient or inpatient settings. Evidence supporting the use of CCP for severe COVID-19 is mixed and still emerging. One major limitation in interpreting published clinical trials and the clinical role of CCP is incomplete understanding of necessary neutralizing antibody (nAb) titer for clinically effective CCP. Observational studies suggest that higher antibody-content CCP is more effective than lower antibody-content CCP, or that very low antibody-content CCP is harmful. We searched PubMed articles published between February 1, 2020, and April 15, 2022, using the terms "COVID-19", "convalescent plasma", "SARS-CoV-2", and "CCP" alone and in combination. Our search yielded 6,468 results which we filtered to 280 and 162 by selecting Clinical Trial and Randomized Controlled Trial article types, respectively. Among these, we identified 25 open-label or blinded efficacy or effectiveness studies in hospitalized patients that were relevant to our study. Preliminary reports show wide variability in the antibody content of CCP used in clinical trials, the assays used to define CCP antibody content, and the estimates of clinical outcomes following CCP therapy for hospitalized patients. Only one study deliberately infused CCP with nAb > 1:640. Post-hoc analyses of potent monoclonal antibody therapy in hospitalized patients in the UK showed survival benefit when monoclonal antibody was infused to patients who had not yet seroconverted by spike antibody ELISA, suggesting that if dosed appropriately, antibody-based therapies may have a role in improving outcomes of severe COVID-19. Added value of this studyThis phase 2 study showed that CCP with high nAb titer (>1:640) provided more rapid recovery to hospital discharge and fewer COVID-19 attributable AEs than CCP with nAb titer between the FDA-recommended minimum standard and 4-fold higher ([&ge;]1:160-1:640). The hazard ratio of time to hospital discharge from baseline through day 55, accounting for death as a competing event, contrasting patients receiving high versus standard CCP titer was 1.94 (95% CI 1.05-3.58). Adjusted hazard ratios of high versus standard titer CCP receipt for time to hospital discharge were consistent with the primary unadjusted findings. Mortality through 55 days was lower in the high titer group, but with a wide confidence interval that did not reach statistical significance. Implications of all available evidenceOur data that CCP with nAb >1:640 expedites recovery of patients admitted with COVID-19 compared with CCP with nAb [&ge;]1:160-1:640 suggests that a threshhold of nAb [&ge;]1:160 may be too low to define CCP as high titer. Analyses in larger CCP trials should consider full reporting of nAb in CCP units administered at individual study participant level, and specifically whether CCP contained nAb >1:640. Further investigation of CCP with nAb >1:640 is warranted given that raising the threshhold of nAb, or a correlative specific anti-spike antibody assay, used to qualify high titer CCP in clinical trials could inform policy guidance and clinical use of CCP.

BackgroundAntibiotic stewardship during stem cell transplantation (SCT) is challenging.. Procalcitonin (PCT) has been employed successfully in critical care patients to safely guide stewardship. However, procalcitonin guided stewardship has not been robustly assessed in SCT recipients. We sought to evaluate the potential utility of PCT to guide antimicrobial de-escalation during engraftment. Methods100 SCT patients were prospectively enrolled in a "strategy trial" and had infectious complications documented. Lab parameters - CBC, BMP, CRP were obtained daily as standard of care (SOC) while PCT was obtained for research purposes. Providers were blinded to PCT results. We compared duration of antimicrobial escalation between actual events (SOC model) and a proposed PCT model. In this hypothetical PCT model, antibiotic de-escalation would occur if CRP remained <100 mg/dl and PCT <0.25 ng/ml after 3 days of escalation. Escalation events were defined as a substitution or addition of an antimicrobial agent after initiation of prophylactic antimicrobials. Results77 patients had escalation events and of these, 33 had bacterial infections. A total of 136 antimicrobial escalations events were identified, and of these only 39(28.7%) were associated with documented infections. The standard of care model had a mean duration (+SD) of 9.08 (+ 6.08) antibiotic days. If the PCT model were employed, the mean duration (+SD) would be 4.44 (+ 6.16) days (p<0.001). The PCT model, however, would have missed 11 infections\ ConclusionProcalcitonin-guided antimicrobial stewardship during autologous stem cell transplantation is feasible however optimization is necessitated for utilization as a tool to guide antibiotic prophylaxis during SCT.

BackgroundTransfusion of convalescent immune plasma (CP) is commonly used in epidemics. Several articles now describe clinical report data of CP for treatment of SARS-CoV-2-induced COVID-19 disease. MethodsA systematic literature review was conducted using the NCBI curated COVID-19 related open-resource literature database LitCovid to identify studies using CP as treatment for COVID-19 patients. We retrieved and curated all COVID-19 related patient and treatment characteristics from previously reported studies. A Poisson model was developed to evaluate the association between age of the patients, older age being the most common risk factor for COVID-19 mortality, and recovery time since CP treatment using data extracted from the literature. ResultsFrom 18,293 identified COVID-19 related articles, we included ten studies reporting results of CP treatment for COVID-19 from a total of 61 patients. Decreased symptoms of severe COVID-19 and clearance of SARS-CoV-2 RNA were the most direct observations. We found that patients over the age of sixty who received CP treatment for COVID-19 had a significantly prolonged recovery estimated by viral clearance (from 10 to 29 days since first dose of CP) compared to younger patients, who recovered from the infection in less than a week after receiving CP treatment. ConclusionsLimited published results on plasma transfusion treatment for COVID-19 disease with concomitant treatments suggest that CP therapy for COVID-19 is well tolerated and effective. First randomized clinical trial results, however, revealed no improvements in recovery time for elderly patients with severe COVID-19 between standard treatment alone and added with convalescent plasma. Accordingly, we argue that older patients may need a significantly longer time for recovery. Further randomized clinical trial data for COVID-19 with rigorous ethical standards is urgently needed.

INTRODUCTIONCOVID-19 convalescent plasma (CCP) transfusion has emerged in the past months as an alternative approach to treat pneumonia cases of SARS-CoV-2. Current evidence regarding characteristics of the plasma product, the titer of neutralizing antibodies (nAbs) in the transfused units, time to onset of intervention, and impact of nAbs produced by the patient are limited and heterogeneous. MATERIAL AND METHODSWe describe the preliminary results of 104 patients with severe pneumonia due to SARS-CoV-2 transfused with CCP at three medical centers in Brazil. All enrolled patients were transfused with doses between 200 mL through 600mL of ABO compatible CCP on days 0-2 after enrolment. Clinical parameters were monitored and nAbs titration was performed using the cytopathic effect-based virus neutralization test with SARS-CoV-2 (GenBank MT126808.1). RESULTSForty-one patients achieved clinical improvement on day 14, and multivariable logistic regression showed that nAbs T (from CCP units transfused) (p= 0.001), nAbs P0 (on day of enrolment) (p=0.009) and use of other supportive therapies (p<0.001) were associated with higher odds for this clinical improvement. Considering ICU length of stay (LOS) and length of mechanical ventilation, in our analysis, nAbs P0 were associated with a significant reduction in ICU LOS (p=0.018) and duration of mechanical ventilation (p<0.001). Administration of CCP after 10 days of symptom onset was associated with increases in ICU length of stay (p<0.001). DISCUSSION/CONCLUSIONDespite the study limitations, our data have shown an association between patients previously acquired nAbs and clinical outcomes. The potential value of timely administration of CCP transfusion before day 10 of disease onset was demonstrated and nAbsP0, but not nAbsT, were associated with ICU LOS, and duration of mechanical ventilation on the improvement of clinical outcomes was also demonstrated. In conclusion, we consider these data are useful parameters to guide future CPP transfusion strategies to COVID-19.

BackgroundDuring severe and critical COVID-19, therapeutic options remain scarce. Among interventions, the use of interleukin-6 receptor inhibitor (IL-6Ri) is especially controversial due to persistent uncertainty about their efficacy and safety. MethodsWe conducted a multicentric retrospective French observational study. All severe or critical COVID-19 requiring hospital admission were included from march 1st 2020 to December 31th 2021. Our main aim was to compare the occurrence of secondary infections function of the administration of IL-6Ri. Digestive, hematological complications and survival were also analyzed. ResultsAmong 2587 patients requiring hospital admission, 1603 had a severe COVID-19 and 984 a critical one requiring ICU admission. 224 received at least one dose of tocilizumab or sarilumab. Incidence of secondary infection was 29.5% in the IL-6Ri group vs. 19.5% without IL-6Ri (unadjusted OR: 1.73 [1.27;2.34]; p = 0.0004) in the whole population. This result remained consistent after adjustment, without multiple imputation (MI) (adjusted OR: 2.12 [1.51; 2.97]; p < 0.0001) and after MI (adjusted OR: 1.47 [1.25; 1.72]; p < 0.0001)). Incidence of hematological or digestive complication were similar between groups. Mortality of patients admitted in ward was higher in the IL-6Ri group (18.7% vs 10.5%, p = 0.0155). No difference in 28 days, ICU, hospital of 90 days mortality was noticed among ICU patients. Conclusionin this population, administration of IL-6Ri was associated with a higher risk of secondary infection in the whole population and with a higher mortality among patients who spent their whole stay in ward.

At the beginning of the COVID-19 pandemic, there was high mortality and a lack of effective treatment for critically ill patients. Build on the experience in argentine hemorrhagic fever with convalescent plasma, we incorporated 90 patients into a multicenter study, and 87 were evaluable. We collected 397 donations from 278 convalescent donors. Patients received plasma with an IgG concentration of 0.7-0.8 (measured by Abbott chemiluminescence) for every 10 kg of body weight. Survival during the first 28 days was the primary objective. 77% were male, age 54 {+/-} 15.6 y/o (range 27-85); body mass index 29.7 {+/-} 4,4; hypertension 39% and diabetes 20%; 19.5% had an immunosuppression condition; 23% were healthcare workers. Plasma was administered to 55 patients (63%) on spontaneous breathing with oxygen supplementation (mainly oxygen mask with reservoir bag in 80%), and 32 patients (37%) were infused on mechanical ventilation. The 28-day survival rate was 80%, with 91% in patients infused on spontaneous breathing and 63% in those infused on mechanical ventilation (p = 0.0002). There was a significant improvement in the WHO pneumonia clinical scale at 7 and 14 days, and in PaO2 / FiO2, ferritin and LDH, in the week post-infusion. We observed an episode of circulatory volume overload and a febrile reaction, both mild. Convalescent plasma infusions are feasible, safe, and potentially effective, especially before requiring mechanical ventilation, and are an attractive clinical option for treating severe forms of COVID-19 until other effective therapies become available.

BackgroundVaccination is an important tool in the fight against pandemics. However, the associated adverse events (AEs) may negatively impact the public perception of vaccines, therefore leading to decreased vaccination willingness. Interestingly, pharmacovigilance data of the three COVID-19 vaccines with a two-dose schedule approved in the EU (AstraZeneca, BioNTech and Moderna) already revealed country-specific differences in their safety profile early on (as of February 2021), at a time when the accumulated occurrence of specific AEs was not yet known. In the safety outcome assessment presented here, we aimed to establish whether these country-specific differences in pharmacovigilance data could be explained by differences in the frequency of AEs as reported in the respective approval studies of each vaccine. MethodsA systematic search was performed to identify all publications regarding the randomized controlled trials (RCTs) of two-dose vaccines approved in the EU (AstraZeneca, BioNTech and Moderna), including regulatory reports and journal articles. All obtained safety data was manually entered into an SQL database. In order to enable the comparability among the data, the solicited AEs for all vaccines (i.e. those AEs actively sought after vaccination) were investigated. The data was standardized to promote comparability and overcome data heterogeneity and complexity. FindingsTwelve documents regarding the RCTs for the three COVID-19 vaccines with a two-dose schedule approved in the EU (AstraZeneca, BioNTech and Moderna) were included in the safety outcome analysis. The entire safety data compiled in the SQL database amounted to 66 different study arms. The data structure revealed 13 different age thresholds or ranges and three different data sets regarding doses (first dose vs. second dose vs. all doses). After standardization and identification of subgroups, the analyses demonstrated that the highest rates of AEs occur after the first dose with the AstraZeneca vaccine, whereas with Moderna and BioNTech most AEs occur after the second dose. Astonishingly, the absolute frequencies of each AE after the first AstraZeneca dose correspond to those of the second dose of the mRNA vaccines (BioNTech and Moderna). Reversely, the absolute frequencies of the same AEs after the second AstraZeneca dose correspond to those of the first dose with the mRNA vaccines. The most common AEs with any vaccine were fatigue, headache and myalgia. Moreover, middle-aged subjects (18 to 55 years) had more side effects than older individuals (> 55 years), an observation that persisted among vaccines. InterpretationThis is the first indirect comparison of these vaccines that uses all available RCT data. The absolute frequency of each AE is similar between the first AstraZeneca dose and the second dose of BioNTech or Moderna; their occurrence was thus independent of platform (vector or mRNA) or the vaccine itself. This assessment demonstrates that the varying frequencies of AEs reported in early pharmacovigilance data for the vaccines in distinct countries, at a time when the accumulated occurrence of specific AEs with certain vaccines was not yet known, cannot be explained by different frequencies being reported in the respective RCTs. ConclusionThe approach presented here could help to objectify future discussions on vaccine preferences. Therefore, it may serve as basis for future public awareness campaigns and may also allow the comparison of vaccine performance in different subgroups (e.g. virus variants, high-risk patients). This approach may also be applied to a broad range of other challenges across the R&D process and various disease categories.

BackgroundTocilizumab treatment is investigated, and effectiveness in ICU-admitted COVID-19 patients has been reported. Although controversy exists regarding the efficacy of tocilizumab treatment, it has been suggested that tocilizumab might show positive results depending on patient severity status. We examined an association between tocilizumab and distinct disease severity stages. Methods and FindingsFrom March 3 to March 23 2020, 494 consecutively admitted COVID-19 patients received tocilizumab or standard treatment alone. Data were obtained retrospectively. Clinical respiratory severity (CRS) stages were defined by patient oxygenation status and were also associated to scores of WHO clinical progression scale. We categorized patients in three stages, mild/moderate CRS1 (FiSpO2<0.35; WHO score 5), moderate/severe CRS2 (FiO2=0.5/high flow mask; WHO score 6) and severe/critical CRS3 (FiO2<80%/high flow/prone position or mechanical ventilation; score>6). The primary outcome was the composite of death or ICU admission in patients of stages CRS1, CRS2, and CRS3, as well as in total patients. We also addressed mortality alone in total patients. Kaplan-Maier curves, Cox proportional regression and inverse probability weighting marginal structural models were used. We conducted the study from March 3 to April 7 2020 with broad-ranged severity patients; 167 tocilizumab-treated and 327 untreated. CRS1 patients showed no apparent benefit after treatment, while the risk of the primary outcome was greatly reduced in CRS2 treated participants ((HR=0.22; 95% CI (0.16-0.44)). Moreover, tocilizumab treatment was associated with significantly decreased CRS2 patient proportion that reached the outcome compared to non-treated controls (27.8.0% vs. 65.4%; p<0.001). Severe/critical CRS3 patients, also showed benefit after treatment (HR=0.38; 95% CI (0.16-90)), although not as robust as was that of CRS2 treated individuals. Tocilizumab was associated with reduced outcome risk in total patients (HR=0.42; 95% CI (0.26-0.66)) after CRS adjustment, but not if CRS classification was not accounted as confounding factor (HR=1.19; 95% CI (0.84-1.69)). The outcome of mortality alone upon tocilizumab treatment was significant (HR=0.58; 95% CI (0.35-0.96)) after accounting for CRS classification. ConclusionsTocilizumab treatment is associated with reduced COVID-19 escalation in CRS2 patients, suggesting efficacy in moderate/severe non-ICU-admitted patients. CRS classification could represent an essential confounding factor in evaluating tocilizumab in studies of broad-ranged severity patients.