COVID-19 Convalescent Plasma Therapy Decreases Inflammatory Cytokines: A Randomized Controlled Trial

This study examined the role that cytokines may have played in the beneficial outcomes found when outpatient individuals infected with SARS-CoV-2 were transfused with COVID-19 convalescent plasma (CCP) early in their infection. We found that the pro-inflammatory cytokine IL-6 decreased significantly faster in patients treated early with CCP. Participants with COVID-19 treated with CCP later in the infection did not have the same effect. This decrease in IL-6 levels after early CCP treatment suggests a possible role of inflammation in COVID-19 progression. The evidence of IL-6 involvement brings insight into the possible mechanisms involved in CCP treatment mitigating SARS-CoV-2 severity

Dynamics of Inflammatory Responses After SARS-CoV-2 Infection by Vaccination Status in the USA: A Prospective Cohort Study

BACKGROUND: Cytokines and chemokines play a critical role in the response to infection and vaccination. We aimed to assess the longitudinal association of COVID-19 vaccination with cytokine and chemokine concentrations and trajectories among people with SARS-CoV-2 infection. METHODS: In this longitudinal, prospective cohort study, blood samples were used from participants enrolled in a multi-centre randomised trial assessing the efficacy of convalescent plasma therapy for ambulatory COVID-19. The trial was conducted in 23 outpatient sites in the USA. In this study, participants (aged ≥18 years) were restricted to those with COVID-19 before vaccination or with breakthrough infections who had blood samples and symptom data collected at screening (pre-transfusion), day 14, and day 90 visits. Associations between COVID-19 vaccination status and concentrations of 21 cytokines and chemokines (measured using multiplexed sandwich immunoassays) were examined using multivariate linear mixed-effects regression models, adjusted for age, sex, BMI, hypertension, diabetes, trial group, and COVID-19 waves (pre-alpha or alpha and delta). FINDINGS: Between June 29, 2020, and Sept 30, 2021, 882 participants recently infected with SARS-CoV-2 were enrolled, of whom 506 (57%) were female and 376 (43%) were male. 688 (78%) of 882 participants were unvaccinated, 55 (6%) were partly vaccinated, and 139 (16%) were fully vaccinated at baseline. After adjusting for confounders, geometric mean concentrations of interleukin (IL)-2RA, IL-7, IL-8, IL-15, IL-29 (interferon-λ), inducible protein-10, monocyte chemoattractant protein-1, and tumour necrosis factor-α were significantly lower among the fully vaccinated group than in the unvaccinated group at screening. On day 90, fully vaccinated participants had approximately 20% lower geometric mean concentrations of IL-7, IL-8, and vascular endothelial growth factor-A than unvaccinated participants. Cytokine and chemokine concentrations decreased over time in the fully and partly vaccinated groups and unvaccinated group. Log INTERPRETATION: Initially and during recovery from symptomatic COVID-19, fully vaccinated participants had lower concentrations of inflammatory markers than unvaccinated participants suggesting vaccination is associated with short-term and long-term reduction in inflammation, which could in part explain the reduced disease severity and mortality in vaccinated individuals. FUNDING: US Department of Defense, National Institutes of Health, Bloomberg Philanthropies, State of Maryland, Mental Wellness Foundation, Moriah Fund, Octapharma, HealthNetwork Foundation, and the Shear Family Foundation

Risk factors for severe illness in hospitalized Covid-19 patients at a regional hospital

BACKGROUND: The Covid-19 pandemic threatens to overwhelm scarce clinical resources. Risk factors for severe illness must be identified to make efficient resource allocations. OBJECTIVE: To evaluate risk factors for severe illness. DESIGN: Retrospective, observational case series. SETTING: Single-institution. PARTICIPANTS: First 117 consecutive patients hospitalized for Covid-19 from March 1 to April 12, 2020. EXPOSURE: None. MAIN OUTCOMES AND MEASURES: Intensive care unit admission or death. RESULTS: In-hospital mortality was 24.8% and average total length of stay was 11.82 days (95% CI: 10.01 to 13.63 days). 30.8% of patients required intensive care unit admission and 29.1% required mechanical ventilation. Multivariate regression identified the amount of supplemental oxygen required at admission (OR: 1.208, 95% CI: 1.011–1.443, p = .037), sputum production (OR: 6.734, 95% CI: 1.630–27.812, p = .008), insulin dependent diabetes mellitus (OR: 11.873, 95% CI: 2.218–63.555, p = .004) and chronic kidney disease (OR: 4.793, 95% CI: 1.528–15.037, p = .007) as significant risk factors for intensive care unit admission or death. Of the 48 patients who were admitted to the intensive care unit or died, this occurred within 3 days of arrival in 42%, within 6 days in 71%, and within 9 days in 88% of patients. CONCLUSIONS: At our regional medical center, patients with Covid-19 had an average length of stay just under 12 days, required ICU care in 31% of cases, and had a 25% mortality rate. Patients with increased sputum production and higher supplemental oxygen requirements at admission, and insulin dependent diabetes or chronic kidney disease may be at increased risk for severe illness. A model for predicting intensive care unit admission or death with excellent discrimination was created that may aid in treatment decisions and resource allocation. Early identification of patients at increased risk for severe illness may lead to improved outcomes in patients hospitalized with Covid-19

Symptom Duration and Resolution With Early Outpatient Treatment of Convalescent Plasma for Coronavirus Disease 2019: A Randomized Trial

Background Coronavirus disease 2019 (COVID-19) convalescent plasma (CCP) reduces hospitalizations among outpatients treated early after symptom onset. It is unknown whether CCP reduces time to symptom resolution among outpatients. Methods We evaluated symptom resolution at day 14 by trial arm using an adjusted subdistribution hazard model, with hospitalization as a competing risk. We also assessed the prevalence of symptom clusters at day 14 between treatments. Clusters were defined based on biologic clustering, impact on ability to work, and an algorithm. Results Among 1070 outpatients followed up after transfusion, 381 of 538 (70.8%) receiving CCP and 381 of 532 (71.6%) receiving control plasma were still symptomatic (P = .78) at day 14. Associations between CCP and symptom resolution by day 14 did not differ significantly from those in controls after adjustment for baseline characteristics (adjusted subdistribution hazard ratio, 0.99; P = .62). The most common cluster consisted of cough, fatigue, shortness of breath, and headache and was found in 308 (57.2%) and 325 (61.1%) of CCP and control plasma recipients, respectively (P = .16). Conclusions In this trial of outpatients with early COVID-19, CCP was not associated with faster resolution of symptoms compared with control. Overall, there were no differences by treatment in the prevalence of each symptom or symptom clusters at day 14. Early treatment with coronavirus disease 2019 convalescent plasma was not associated with faster symptom resolution than control treatment, in contrast with decreased hospitalization in the same population, suggesting that the timing antibody treatment may affect hospitalization and symptom progression differently

COVID-19 Convalescent Plasma Outpatient Therapy to Prevent Outpatient Hospitalization: A Meta-analysis of Individual Participant Data From Five Randomized Trials

BACKGROUND: Outpatient monoclonal antibodies are no longer effective and antiviral treatments for COVID-19 disease remain largely unavailable in many countries worldwide. Although treatment with COVID-19 convalescent plasma is promising, clinical trials among outpatients have shown mixed results. METHODS: We conducted an individual participant data meta-analysis from outpatient trials to assess the overall risk reduction for all-cause hospitalizations by day 28 in transfused participants. Relevant trials were identified by searching MEDLINE, Embase, MedRxiv, World Health Organization, Cochrane Library, and Web of Science from January 2020 to September 2022. RESULTS: Five included studies from four countries enrolled and transfused 2,620 adult patients. Comorbidities were present in 1,795 (69%). The virus neutralizing antibody dilutional titer levels ranged from 8 to 14,580 in diverse assays. 160 (12.2%) of 1315 control patients were hospitalized, versus 111 (8.5%) of 1305 COVID-19 convalescent plasma treated patients, yielding a 3.7% (95%CI: 1.3%-6.0%; p=.001) absolute risk reduction and 30.1% relative risk reduction for all-cause hospitalization. The hospitalization reduction was greatest in those with both early transfusion and high titer with a 7.6% absolute risk reduction (95%CI: 4.0%-11.1%; p=.0001) accompanied by at 51.4% relative risk reduction. No significant reduction in hospitalization was seen with treatment > 5 days after symptom onset or in those receiving COVID-19 convalescent plasma with antibody titers below the median titer. CONCLUSIONS: Among outpatients with COVID-19, treatment with COVID-19 convalescent plasma reduced the rate of all-cause hospitalization and may be most effective when given within 5 days of symptom onset and when antibody titer is higher

High Viral Specific Antibody Convalescent Plasma Effectively Neutralizes SARS-CoV-2 Variants of Concern

The ongoing evolution of SARS-Co-V2 variants to omicron severely limits available effective monoclonal antibody therapies. Effective drugs are also supply limited. Covid-19 convalescent plasma (CCP) qualified for high antibody levels effectively reduces immunocompetent outpatient hospitalization. The FDA currently allows outpatient CCP for the immunosuppressed. Viral specific antibody levels in CCP can range ten-to hundred-fold between donors unlike the uniform viral specific monoclonal antibody dosing. Limited data are available on the efficacy of polyclonal CCP to neutralize variants. We examined 108 pre-delta/pre-omicron donor units obtained before March 2021, 20 post-delta COVID-19/post-vaccination units and one pre-delta/pre-omicron hyperimmunoglobulin preparation for variant specific virus (vaccine-related isolate (WA-1), delta and omicron) neutralization correlated to Euroimmun S1 IgG antibody levels. We observed a 2-to 4-fold and 20-to 40-fold drop in virus neutralization from SARS-CoV-2 WA-1 to delta or omicron, respectively. CCP antibody levels in the upper 10% of the 108 donations as well as 100% of the post-delta COVID-19/post-vaccination units and the hyperimmunoglobulin effectively neutralized all three variants. High-titer CCP neutralizes SARS-CoV-2 variants despite no previous donor exposure to the variants. Key pointsAll of the post-delta COVID-19/post vaccination convalescent plasma effectively neutralizes the omicron and delta variants.High-titer CCP and hyperimmunoglobulin neutralizes SARS-CoV-2 variants despite no previous donor exposure to the variants