COVID-19 convalescent plasma for the treatment of immunocompromised patients: a systematic review.

Immunosuppressed patients have increased risk for morbidity and mortality from COVID-19 because they less frequently mount antibody responses to vaccines and often cannot tolerate small-molecule antivirals. The Omicron variant of concern of SARS-CoV-2 has progressively defeated anti-Spike mAbs authorized so far, paving the way to a return to COVID-19 convalescent plasma (CCP) therapy. In this systematic review we performed a metanalysis of 9 controlled studies (totaling 535 treated patients and 1365 controls and including 4 randomized controlled trials), an individual patient data analysis of 125 case reports/series (totaling 265 patients), and a descriptive analysis of 13 uncontrolled large case series without individual patient data available (totaling 358 patients). The metanalysis of controlled studies showed a risk ratio for mortality of 0.65 (risk difference -0.11) in treatment with CCP versus standard of care for immunosuppressed COVID-19 patients. On the basis of this evidence, we encourage initiation of high-titer CCP from vaccinees( hybrid plasma) in immunocompromised patients.

COMPARATIVE ANALYSIS OF ANTIBODY RESPONSES FROM COVID-19 CONVALESCENTS RECEIVING VARIOUS VACCINES REVEALS CONSISTENT HIGH NEUTRALIZING ACTIVITY FOR SARS-CoV-2 VARIANT OF CONCERN OMICRON.

The latest SARS-CoV-2 variant of concern Omicron, with its immune escape from therapeutic anti-Spike monoclonal antibodies and WA-1 vaccine-elicited sera, demonstrates the continued relevance of COVID- 19 convalescent plasma (CCP) therapies. Lessons learnt from previous usage of CCP suggests focusing on early outpatients and immunocompromised recipients, with high neutralizing antibody (nAb) titer units. In this analysis we systematically reviewed Omicron-neutralizing plasma activity data, and found that approximately 47% (424/902) of CCP from unvaccinated pre-Omicron donors neutralizes Omicron BA.1 with a very low geomean of geometric mean titers for 50% neutralization GM(GMT50) of about 13, representing a more than 20-fold reduction from WA-1 neutralization. Two doses of mRNA vaccines in nonconvalescent subjects had a similar 50% percent neutralization with Omicron BA.1 neutralization GM(GMT(50)) of about 27. However, plasma from vaccinees recovered from either previous pre-Omicron variants of concern infection, Omicron BA.1 infection, or third-dose uninfected vaccinees was nearly 100% neutralizing against Omicron BA.1, BA.2 and BA.4/5 with GM(GMT(50)) all over 189, 10 times higher than pre-Omicron CCP. Fully vaccinated and post-BA.1 plasma (Vax-CCP) had GM(GMT50) over 450 for BA.4/5 and over 1500 for BA.1 and BA.2. These findings have implications for both CCP stocks collected in prior pandemic periods and plans to restart CCP collections. Thus, Vax-CCP provides an effective tool to combat ongoing variants that defeat therapeutic monoclonal antibodies.

COVID-19 convalescent plasma and randomized clinical trials: rebuilding confidence by explaining failures and finding signals of efficacy.

Convalescent plasma (CP) recurs as a frontline treatment in epidemics because it is available as soon as there are survivors. The COVID-19 pandemic represented the first large-scale opportunity to shed light into mechanisms of action, safety and efficacy of CP using modern evidence-based medicine approaches. Studies ranging from observational case series to randomized controlled trials (RCT) have reported highly variable efficacy results for COVID-19 CP (CCP), resulting in uncertainty. Reasons for CCP success and failure may be hidden in study details, which are usually difficult to explain to physicians and the public but provide fertile ground for designing next-generation studies. We analyzed variables associated with efficacy such as clinical settings, disease severity, CCP SARS-CoV-2 antibody levels and function, dose, timing of administration (variously defined as time from onset of symptoms, molecular diagnosis, diagnosis of pneumonia, or hospitalization, or by serostatus), outcomes (defined as hospitalization, requirement for ventilation, clinical improvement or mortality), CCP provenance and time for collection, and criteria for efficacy. Focusing only on the results from the 30 available RCTs we noted that these were more likely to show signals of efficacy, including reductions in mortality, if the plasma neutralizing titer was [≥] 160 and the time to randomization was [≤] 9 days, consistent with passive antibody therapy efficacy requiring dosing with sufficient antibody. The fact that most studies revealed signals of efficacy despite variability in CCP and its use suggest likely therapeutic effects that become apparent despite the data noise. Despite the recent WHO guidelines discouraging CCP usage, the Omicron variant of concern is reminding us the superiority of polyclonal antibody therapies over monoclonal antibodies, and CCP from vaccinated convalescents is likely to be evaluated soon

Program and patient characteristics for the United States Expanded Access Program to COVID-19 convalescent plasma

BackgroundThe United States (US) Expanded Access Program (EAP) to COVID-19 convalescent plasma was initiated in response to the rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease-2019 (COVID-19). While randomized clinical trials were in various stages of development and enrollment, there was an urgent need for widespread access to potential therapeutic agents particularly for vulnerable racial and ethnic minority populations who were disproportionately affected by the pandemic. The objective of this study is to report on the demographic, geographic, and chronological access to COVID-19 convalescent plasma in the US via the EAP. Methods and findingsMayo Clinic served as the central IRB for all participating facilities and any US physician could participate as local physician-principal investigator. Registration occurred through the EAP central website. Blood banks rapidly developed logistics to provide convalescent plasma to hospitalized patients with COVID-19. Demographic and clinical characteristics of all enrolled patients in the EAP were summarized. Temporal trends in access to COVID-19 convalescent plasma were investigated by comparing daily and weekly changes in EAP enrollment in response to changes in infection rate on a state level. Geographical analyses on access to convalescent plasma included assessing EAP enrollment in all national hospital referral regions as well as assessing enrollment in metropolitan and less populated areas which did not have access to COVID-19 clinical trials. From April 3 to August 23, 2020, 105,717 hospitalized patients with severe or life-threatening COVID-19 were enrolled in the EAP. A majority of patients were older than 60 years of age (57.8%), male (58.4%), and overweight or obese (83.8%). There was substantial inclusion of minorities and underserved populations, including 46.4% of patients with a race other than White, and 37.2% of patients were of Hispanic ethnicity. Severe or life-threatening COVID-19 was present in 61.8% of patients and 18.9% of patients were mechanically ventilated at time of convalescent plasma infusion. Chronologically and geographically, increases in enrollment in the EAP closely followed confirmed infections across all 50 states. Nearly all national hospital referral regions enrolled patients in the EAP, including both in metropolitan and less populated areas. ConclusionsThe EAP successfully provided widespread access to COVID-19 convalescent plasma in all 50 states, including for underserved racial and ethnic minority populations. The efficient study design of the EAP may serve as an example framework for future efforts when broad access to a treatment is needed in response to a dynamic disease affecting demographic groups and areas historically underrepresented in clinical studies.

Convalescent Plasma Use in the United States was inversely correlated with COVID-19 Mortality: Did Convalescent Plasma Hesitancy cost lives?

The US Food and Drug Administration (FDA) authorized treatment of hospitalized COVID-19 patients with Convalescent Plasma (CCP) via the Expanded Access Program (EAP) and the Emergency Use Authorization (EUA), leading to the use of CCP in some 500,000 patients during the first year of the pandemic. We tracked the number of CCP units dispensed to hospitals by blood banking organizations and correlated that usage with hospital admission and mortality data over the course of the year. CCP usage per admission peaked after issuance of the EUA, with more than 40% of inpatients estimated to have received CCP between late September and early November 2020. However, following reports of randomized controlled trials that failed to show clear benefit from CCP, usage/admissions declined steadily to a nadir of less than 10% in March 2021. We found a strong inverse correlation (Pearsons correlation coefficient of -0.5176 with P = 0.00242) between CCP usage/hospital admission and deaths occurring two weeks after admission, and this finding was robust to examination of deaths taking place one, two or three weeks after admission. Changes in the number of hospital admissions, prevalence of variants, and age of patients could not explain these findings. We estimate that the retreat from CCP usage, a phenomenon we termed plasma hesitancy, might have resulted in 29,000 to 36,000 excess deaths in the period from mid-November 2020 to February 2021. These results highlight the need for additional studies to ascertain the variables associated with efficacy and/or provide other explanations for the robust relationships observed in this study.

Mortality in individuals treated with COVID-19 convalescent plasma varies with the geographic provenance of donors

Treatment and prevention of coronavirus disease 2019 (COVID-19) have attempted to harness the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) including the development of successful COVID-19 vaccines and therapeutics (e.g., Remdesivir, convalescent plasma [CP]). Evidence that SARS-CoV-2 exists as quasispecies evolving locally suggests that immunological differences may exist that could impact the effectiveness of antibody-based treatments and vaccines. Regional variants of SARS-CoV-2 were reported in the USA beginning in November 2020 but were likely present earlier. There is available evidence that the effectiveness of CP obtained from donors infected with earlier strains in the pandemic may be reduced when tested for neutralization against newer SARS-Cov-2 variants. Using data from the Expanded Access Program to convalescent plasma, we used a gradient-boosting machine to identify predictors of 30-day morality and a series of regression models to estimate the relative risk of death at 30 days post-transfusion for those receiving near sourced plasma (defined as plasma transported [≤] 150 miles) vs. distantly sourced plasma (> 150 miles). Our results show a lower risk of death at 30 days post-transfusion for near sourced plasma. Additional analyses stratified by disease severity, time to treatment, and donor region further supported these findings. The results of this study suggest that near sourced plasma is superior to distantly sourced plasma, which has implications for interpreting the results of clinical studies and designing effective treatment of COVID-19 patients as additional local variant are likely to emerge.

Convalescent Plasma and Improved Survival in Patients with Hematologic Malignancies and COVID-19

Convalescent plasma may benefit immunocompromised individuals with COVID-19, including those with hematologic malignancy. We evaluated the association of convalescent plasma treatment with 30-day mortality in hospitalized adults with hematologic malignancy and COVID-19 from a multi-institutional cohort. 143 treated patients were compared to 823 untreated controls. After adjustment for potential confounding factors, convalescent plasma treatment was associated with improved 30-day mortality (hazard ratio, 0.60; 95% CI, 0.37-0.97). This association remained significant after propensity-score matching (hazard ratio, 0.52; 95% CI, 0.29-0.92). These findings suggest a potential survival benefit in the administration of convalescent plasma to patients with hematologic malignancy and COVID-19.

The Role of Disease Severity and Demographics in the Clinical Course of COVID-19 Patients Treated with Convalescent Plasma

Treatment of patients with COVID-19 using convalescent plasma from recently recovered patients has been shown to be safe, but the time course of change in clinical status following plasma transfusion in relation to baseline disease severity has not yet been described. We analyzed short, descriptive daily reports of patient status in 7,180 hospitalized recipients of COVID-19 convalescent plasma in the Mayo Clinic Expanded Access Program. We assessed, from the day following transfusion, whether the patient was categorized by his or her physician as better, worse or unchanged compared to the day before, and whether, on the reporting day, the patient received mechanical ventilation, was in the ICU, had died or had been discharged. Most patients improved following transfusion, but clinical improvement was most notable in mild to moderately ill patients. Patients classified as severely ill upon enrollment improved, but not as rapidly, while patients classified as critically ill/end-stage and patients on ventilators showed worsening of disease status even after treatment with convalescent plasma. Patients age 80 and over showed little or no clinical improvement following transfusion. Clinical status at enrollment and age appear to be the primary factors in determining the therapeutic effectiveness of COVID-19 convalescent plasma among hospitalized patients.

Therapeutic use of convalescent plasma in COVID-19 patients with immunodeficiency: A systematic review

0In the absence of effective countermeasures, human convalescent plasma has been widely used to treat severe acute respiratory syndrome coronavirus 2 including among patients with innate or acquired immunodeficiency. However, the association between COVID-19-associated mortality in patients with immunodeficiency and therapeutic use of convalescent plasma is unknown. We review clinical features and treatment protocols of COVID-19 patients with immunodeficiency after treatment with human convalescent plasma. We also discuss the time course and clinical features of recovery. These insights provide evidence for the need to develop a clear treatment protocol for COVID-19 patients with immunodeficiency and support the efficacy of convalescent plasma in patients with primary or secondary immunodeficiency.

Effect of Convalescent Plasma on Mortality among Hospitalized Patients with COVID-19: Initial Three-Month Experience

ImportancePassive antibody transfer is a longstanding treatment strategy for infectious diseases that involve the respiratory system. In this context, human convalescent plasma has been used to treat coronavirus disease 2019 (COVID-19), but the efficacy remains uncertain. ObjectiveTo explore potential signals of efficacy of COVID-19 convalescent plasma. DesignOpen-label, Expanded Access Program (EAP) for the treatment of COVID-19 patients with human convalescent plasma. SettingMulticenter, including 2,807 acute care facilities in the US and territories. ParticipantsAdult participants enrolled and transfused under the purview of the US Convalescent Plasma EAP program between April 4 and July 4, 2020 who were hospitalized with (or at risk of) severe or life threatening acute COVID-19 respiratory syndrome. InterventionTransfusion of at least one unit of human COVID-19 convalescent plasma using standard transfusion guidelines at any time during hospitalization. Convalescent plasma was donated by recently-recovered COVID-19 survivors, and the antibody levels in the units collected were unknown at the time of transfusion. Main Outcomes and MeasuresSeven and thirty-day mortality. ResultsThe 35,322 transfused patients had heterogeneous demographic and clinical characteristics. This cohort included a high proportion of critically-ill patients, with 52.3% in the intensive care unit (ICU) and 27.5% receiving mechanical ventilation at the time of plasma transfusion. The seven-day mortality rate was 8.7% [95% CI 8.3%-9.2%] in patients transfused within 3 days of COVID-19 diagnosis but 11.9% [11.4%-12.2%] in patients transfused 4 or more days after diagnosis (p<0.001). Similar findings were observed in 30-day mortality (21.6% vs. 26.7%, p<0.0001). Importantly, a gradient of mortality was seen in relation to IgG antibody levels in the transfused plasma. For patients who received high IgG plasma (>18.45 S/Co), seven-day mortality was 8.9% (6.8%, 11.7%); for recipients of medium IgG plasma (4.62 to 18.45 S/Co) mortality was 11.6% (10.3%, 13.1%); and for recipients of low IgG plasma (<4.62 S/Co) mortality was 13.7% (11.1%, 16.8%) (p=0.048). This unadjusted dose-response relationship with IgG was also observed in thirty-day mortality (p=0.021). The pooled relative risk of mortality among patients transfused with high antibody level plasma units was 0.65 [0.47-0.92] for 7 days and 0.77 [0.63-0.94] for 30 days compared to low antibody level plasma units. Conclusions and RelevanceThe relationships between reduced mortality and both earlier time to transfusion and higher antibody levels provide signatures of efficacy for convalescent plasma in the treatment of hospitalized COVID-19 patients. This information may be informative for the treatment of COVID-19 and design of randomized clinical trials involving convalescent plasma. Trial RegistrationClinicalTrials.gov Identifier: NCT04338360 Key PointsO_ST_ABSQuestionC_ST_ABSDoes transfusion of human convalescent plasma reduce mortality among hospitalized COVID-19 patients? FindingsTransfusion of convalescent plasma with higher antibody levels to hospitalized COVID-19 patients significantly reduced mortality compared to transfusions with low antibody levels. Transfusions within three days of COVID-19 diagnosis yielded greater reductions in mortality. MeaningEmbedded in an Expanded Access Program providing access to COVID-19 convalescent plasma and designed to assess its safety, several signals consistent with efficacy of convalescent plasma in the treatment of hospitalized COVID-19 patients emerged.

Evidence favouring the efficacy of convalescent plasma for COVID-19 therapy

To determine the effect of COVID-19 convalescent plasma on mortality, we aggregated patient outcome data from randomized clinical trials, matched control, case series, and case report studies. Fixed-effects analyses demonstrated that hospitalized COVID-19 patients transfused with convalescent plasma exhibited a ~57% reduction in mortality rate (10%) compared to matched-patients receiving standard treatments (22%; OR: 0.43, P < 0.001). These data provide evidence favouring the efficacy of human convalescent plasma as a therapeutic agent in hospitalized COVID-19 patients.