ABSTRACT
Background: Blood product in therapeutic transfusion are now commonly acknowledged to present biologically active constituents during processes of preparation. In the midst of worldwide COVI-19 pandemic, preliminary evidence, suggest that convalescent plasma may lessen the severity of COVID-19, particularly concerning patients with profound B-cell lymphopenia and prolonged COVID-19 symptoms. Aim(s): This study examined the influence of photochemical pathogen reduction treatment (PRT) using amotosalen-HCl and UVA light vs untreated control convalescent plasma (n = 72 -paired samples) -cFFP. Method(s): This study investigated the soluble inflammatory factors: SCD40L, IFN-alpha, IFN-beta, IFN-gamma, IL-1 beta, IL-6, IL-8, IL-10, IL-18, TNF-alpha and ex-vivo inflammatory bioactivity on endothelial cells. Result(s): We observed that IL-8 concentrations were significantly decreased in cFFP w PRT, whereas IL-18 concentration was increased. We observed after activation with cFFP w PRT and w/o PRT no significant modulation of IL-6 released by endothelial cells. CD54 and CD31 expression in the presence of cFFP (w or w/o PRT) is close to negative controls, even if CD54 and CD31 were significant decreased in presence of cFFP w vs w/o PRT. Conclusion(s): It appears valuable to carry on investigations, of IL-18 and IL-8, on both the physiopathology of PRT convalescent plasma treated and post marketing clinical trials. Further research, including a careful clinical evaluation of CCP-treated patients, will be required to further define the clinical relevance of these findings.
ABSTRACT
Background: COVID-19 convalescent plasma (CCP) contains neutralizing anti-SARS- CoV- 2 antibodies that may be useful as COVID-19 passive immunotherapy in patients at risk of developing severe disease. Aim(s): Such plasma from convalescent patients may also have additional immune-modulatory properties when transfused to COVID-19 patients. Method(s): CCP (n = 766) were compared to control non-convalescent plasma (n = 166) for soluble inflammatory markers, ex-vivo inflammatory bioactivity on endothelial cells, neutralizing auto-Ab to type I IFNs, and reported adverse events in the recipients. Result(s): CCP exhibited significantly higher IL-6 and TNF-alpha (0.531+/-0.04 vs 0.271+/-0.04;p = 0.0061 and 0.900+/-0.07 vs 0.283+/-0.07 pg/ml;p < 0.0001), respectively) and lower IL-10 (0.731+/-0.07 vs 1.22+/-0.19 pg/ ml, p = 0.0034) levels than control plasma. Other inflammatory markers as well as ex-vivo bioactivity did not differ significantly between CCP and control plasma. Neutralizing auto-Abs against type I IFNs were detected in 14/766 (1.8 %) CCP. They were not associated with reported adverse events when transfused (n = 14). Inflammatory markers and bioactivity in CCP with or without auto-Ab, or in CCP associated or not with adverse events in transfused patients, did not differ significantly. Overall, CCP exhibited moderately increased inflammatory markers compared to control plasma with no discernable differences in ex-vivo bioactivity. Auto-Ab to type I IFNs, detected in a small fraction of CCP, were not associated with reported adverse events or differences in inflammatory markers. Conclusion(s): Further defining the clinical relevance of these findings will require further studies including careful clinical evaluation of patients treated with CCP.
ABSTRACT
Background: SARS-CoV-2 antibody tests are variable using different antigens, reagent dilutions and units of reporting. Without calibration interlaboratory interpretation of assay results is not possible, SARS-CoV-2 antibody tests are variable using different antigens, reagent dilutions and units of reporting. Without calibration interlaboratory interpretation of assay results is not possible, slowing down progress in treatments with convalescent plasma. slowing down progress in treatments with convalescent plasma. Aims: The aim of this study, which is part of the SUPPORT-E consortium (Supporting high-quality evaluation of COVID-19 convalescent plasma throughout Europe), was to calibrate anti-SARS-CoV-2 antibody assays used by European laboratories to determine antibody titers in (convalescent) plasma. Methods: To achieve this we distributed a set of 23 reference samples to 26 participating blood establishments across Europe. This set served as a quality control round for SARS-CoV-2 antibody testing and consisted of SARS-CoV-2 pre-outbreak negative plasma samples and plasma samples from unvaccinated convalescent donors with low, medium, high and very high IgG titers against the receptor binding domain (RBD) of the SARS-CoV-2 Spike (S) protein. In addition, a serial dilution of one batch of pooled plasma (n = 3) was distributed that could serve as internal standard. This methodology allowed calibration to the WHO standard in IU/ml, so conversion factors could be calculated. Results: Twenty laboratories participated, including the qualitative Euroimmune (n = 7), Roche (n = 4) and Abbott (n = 4) SARS-CoV-2 IgG assay as most frequently used tests. Four laboratories, using commercial assays from WANTAI or DiaSorin, were not able to discriminate pre-outbreak samples from SARS-CoV-2 positive sera. In addition, the majority of the laboratories were not able to discriminate between plasma samples with high and very high titers, showing that the dynamic range of these commercial assays is limited. Using these data we calculated the conversion factor to IU/ml for the qualitative Euroimmune as 238, Roche as 0.98 and for the Abbott test as 0.9, which only applies when pre-vaccinated samples are used in the test. Summary/Conclusions: This initiative by the SUPPORT-E consortium aids in calibration of antibody testing across laboratories, allowing to compare SARS-CoV-2 antibody titers in (convalescent) plasma. For example, our conversion factor can now be used to calibrate Euroimmune units that were measured in the convalescent plasma samples within the Recovery (United Kingdom)1 Capsid (Germany)2 and CovEarly (Netherlands)3 clinical trial. .
ABSTRACT
Background: The efficacy of COVID-19 convalescent plasma (CCP) as passive immunotherapy in hospitalized COVID-19 patients remains uncertain. The transfusion of a large volume of high titre CCP in recently hospitalized patients may be beneficial. Aims: To evaluate the ability CCP transfusion to improve early outcome in patients with moderate to severe COVID-19 pneumonia. Methods: The CORIPLASM study was a multicentric, open-label, Bayesian randomized, adaptive, phase 2/3 clinical trial, nested within the CORIMUNO-19 cohort, to test a superiority hypothesis. Patients 18 years or older hospitalized with COVID-19 in 14 French centers, requiring at least 3 L/min of oxygen but without mechanic ventilation assistance and a WHO Clinical progression scale [CPS, 1 to 10] of 4 or 5 were enrolled. Patients were randomly assigned (1:1) via a web-based system, according to a randomization list stratified on center, to receive usual care plus 4 units of CCP (2 units/day over 2 days) (CCP group) or usual care alone (usual care group) on day 1 and 2 post-enrollment. Primary outcomes were the proportion of patients withWHO CPS greater than 5 on the 10-point scale on day 4 and survival without ventilation or additional immunomodulatory treatment by day 14. Results: One hundred and twenty patients were recruited from April 16th 2020 and April 21th 2021 and randomly assigned to the CCP group (n = 60) and to the usual care group (n = 60) and followed up for 28 days. Immunosuppressed patients comprised 43% (26/60) and 50% (30/60) of patients in the CCP and usual care groups, respectively. Median time from symptoms onset to randomization (days) was 7.0 [interquartile range (IQR): 5.0-9.0] in the CCP group and 7.0 [IQR: 4.0- 8.5] in the usual care group. Thirteen (22%) patients in the CCP group had a WHO CPS greater than 5 at day 4 versus 8 (13%) in the usual care group (adjusted odds ratio (OR): 1.88 [95% CI: 0.71 to 5.24]. By day 14, 19 (31.6%) patients in the CCP and 20 (33.3%) patients in the usual care group had needed ventilation, additional immunomodulatory treatment or had died (adjusted HR: 1.04 [95% CI: 0.55 to 1.97]). The cumulative incidence of death was 3 (5%) in the CCP group and 8 (13%) in the usual care group at day 14 (adjusted HR: 0.40 [95% CI: 0.10 to 1.53]), and 7 (12%) in the CCP group and 12 (20%) in the usual care group at day 28 (adjusted HR: 0.51 [95% CI: 0.20 to 1.32]). Frequency of severe adverse events did not differ significantly between both treatment arms. Subgroup analysis revealed that mortality at day 28 was mostly observed in the immunosuppressed patients (15/56 vs. 4/64) and that CCP was associated with less mortality in these patients (4/26 in the CCP group vs. 11/30 in the usual care group)(HR: 0.36 [95% CI: 0.14-0.97]). Summary/Conclusions: CCP treatment did not improve early outcome in patients with moderate-to-severe COVID-19 pneumonia. CCP-associated early respiratory worsening as well as CCP-associated reduced D14 and D28 mortality were observed, while not reaching statistical significance. CCP treatment was associated with reduced D28 mortality in immunosuppressed patients.
ABSTRACT
Background: Several studies have evaluated COVID-19 convalescent plasma (CCP)'s safety and effectiveness in the prevention of severe COVID-19's worsening. Some of these studies have shown a trend for its efficacy in immunosuppressed patients and that CCP was safe. These studies were performed before the emergence of Omicron variant of SARS-CoV-2, which appeared in December 2021 in France. Aims: All CCP transfusions in France have been performed in a monitored use protocol allowed by the national agency of drug and blood components safety (ANSM). After giving their consent to be transfused, patients were followed to assess this compassionate therapy. All CCPs were qualified with a high titre of antibody, either by seroneutralization (SN) or an ELISA based surrogate for SN. We describe results of this follow-up with a focus on omicron infection. Methods: Consultative multidisciplinary meeting validated the indication for CCP and the order of a medical prescription of CCP. All CCP demands were sent to the EFS medical department to be pseudonymized. Initial and follow-up data of cases were recorded as requested for an assessment. Variables were analysed in relation with the last available follow-up. Results: From May 2020 to the end of February 2022, 1539 patients had received CCP, of whom 455 had an available follow-up more than 24 h after the last CCP transfusion. Most of them (99.8%) have got a comorbidity: 62.6% have a malignant hemopathy and 19.3% an auto-immune pathology. Among the At the time of CCP request, majority of patients (76.9%) were hospitalized without mechanical ventilation (MV), 18.2% were intubated and a few were not hospitalized for COVID-19 (1.3%) but for another reason. At the last available follow-up, 26.2% were dead but the majority (40.9%) have left the hospital, 23.7% were hospitalized without MV and 9.2% were intubated. Variables associated with a decreased percentage of death were: • The young age (p < 0.0001;N = 455) and the female gender (p = 0.0177;N = 455). • The better state at the time of CCP request (p < 0.0001;N = 439). • The longer delay between the beginning of symptoms and the transfusion (p = 0.0023;N = 445). • A trend was observed for immunosuppression, but it did not reach statistical significance (p = 0.0548;N = 346). There were no difference between Infection due to Omicron variant compared to other variants (p = 0.1560;N = 443). However, follow-up was available in only 33 patients infected with omicron (32.7% of transfused patients infected with omicron) while it was available in 410 patients infected with others SARS-CoV-2 variants (94.4%). Among all transfused patients, 75 adverse events (AE) were reported in 1539 patients (4.8%). Imputability was excluded for 11. Allergy was the most frequent (N = 26;34.6% of AE) always scored as not severe, TACO have occurred in 8 patients, with possible or likely imputability, and TRALI have occurred in 3 patients with possible imputability in 2 cases and non evaluable in one case. Summary/Conclusions: CCP transfusion was more effective when the patient were in better state at the time of CCP request and in immunocompromised than in immunocompetent patients, but this was not statistically significant. Due to the low number of patients infected with omicron with an available follow-up at this day, no conclusion can be drawn on survival of these patients versus patients infected with previous variants.