Mortality rates among hospitalized patients with COVID-19 treated with convalescent plasma: A Systematic review and meta-analysis (preprint)

Abstract IMPORTANCE. Many hospitalized patients with COVID-19 have been treated with convalescent plasma. However, it is uncertain whether this therapy lowers mortality and if so, if the mortality benefit is larger among specific subgroups, such as recipients of plasma with high antibody content and patients treated early in the disease course. OBJECTIVE. To examine the association of COVID-19 convalescent plasma transfusion with mortality and the differences between subgroups in hospitalized patients with COVID-19. DATA SOURCES. On October 26, 2022, a systematic search was performed for clinical studies of COVID-19 convalescent plasma in the literature. STUDY SELECTION. Randomized clinical trials and matched cohort studies investigating COVID-19 convalescent plasma transfusion compared with standard of care treatment or placebo among hospitalized patients with confirmed COVID-19 were included. The electronic search yielded 3,841 unique records, of which 744 were considered for full-text screening. The selection process was performed independently by a panel of five reviewers. DATA EXTRACTION AND SYNTHESIS. The study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Data were extracted by 5 independent reviewers in duplicate and pooled using inverse-variance random-effects model. MAIN OUTCOMES AND MEASURES. Prespecified end point was all-cause mortality during hospitalization. RESULTS. Thirty-nine randomized clinical trials enrolling 21,529 participants and 70 matched cohort studies enrolling 50,160 participants were included in the systematic review. Separate meta-analyses demonstrated that transfusion of COVID-19 convalescent plasma was associated with a significant decrease in mortality compared with the control cohort for both randomized clinical trials (odds ratio (OR), 0.87 [95% CI, 0.76-1.00]) and matched cohort studies (OR, 0.77 [95% CI, 0.64-0.94]). Meta-analysis of subgroups revealed two important findings. First, treatment with convalescent plasma containing high antibody levels was associated with a decrease in mortality compared to convalescent plasma containing low antibody levels (OR, 0.85 [95% CI, 0.73 to 0.99]). Second, earlier treatment with COVID-19 convalescent plasma was associated with a significant decrease in mortality compared with the later treatment cohort (OR, 0.63 [95% CI, 0.48 to 0.82]). CONCLUSIONS AND RELEVANCE. COVID-19 convalescent plasma use was associated with a 13% reduced risk in mortality, implying a mortality benefit for hospitalized patients with COVID-19, particularly those treated with convalescent plasma containing high antibody levels treated earlier in the disease course.

The Female Predominant Persistent Immune Dysregulation of the Post COVID Syndrome: A Cohort Study (preprint)

ObjectiveTo describe the clinical data from the first 107 patients seen in the Mayo Clinic Post COVID-19 Care Clinic (PCOCC). Patients and MethodsAfter IRB approval, we reviewed the charts of 107 patients seen between January 19, 2021 and April 29, 2021 in the Mayo Clinic Post COVID Care Clinic (PCOCC) in order to describe the first 107 patients treated through the Mayo Clinic PCOCC. Data was abstracted from the electronic medical record into a standardized database to facilitate analysis. Phenotypes of patients seen in the PCOCC clinic were identified by expert review of predominant symptom clusters. ResultsThe majority of patients seen in our clinic were female (75%, 80/107), and the median age at presentation was 47 years (interquartile range [IQR] 37, 55). All had Post Acute Sequelae of SARS-CoV-2 infection (PASC) with six clinical phenotypes being identified - fatigue predominant (n=68), dyspnea predominant (n=23), myalgia predominant (n=6), orthostasis predominant (n=6), chest pain predominant (n=3), and headache predominant (n=1). The fatigue-predominant phenotype was more common in women (84%, p=0.006) and the dyspnea-predominant phenotype was more common in men (52%, p=0.002). IL-6 was elevated in 61% of patients (69% of women, p=0.0046) which was statistically discordant with elevation in CRP and ESR which was identified in 17% and 20% of cases respectively (p<0.001). Four PASC phenotypes (fatigue-predominant, myalgia-predominant, orthostasis predominant, and headache-predominant) were associated with central sensitization (CS), and higher IL-6 levels than those phenotypes not associated with CS (p=0.013). Patients with CS phenotypes after COVID-19 infection (post COVID syndrome) were predominantly female (80%, p=0.0085). ConclusionIn our post COVID clinic, we observed several distinct clinical phenotypes. Fatigue-predominance was the most common presentation and was associated with elevated IL-6 levels and female gender. Dyspnea-predominance was more common in men and was not associated with elevated IL-6 levels. IL-6 levels were significantly elevated in patients with PASC and discordant with ESR and CRP, particularly in those with central sensitization phenotypes.

A Hierarchical Bayesian Model for Stochastic Spatiotemporal SIR Modeling and Prediction of COVID-19 Cases and Hospitalizations (preprint)

Most COVID-19 predictive modeling efforts use statistical or mathematical models to predict national- and state-level COVID-19 cases or deaths in the future. These approaches assume parameters such as reproduction time, test positivity rate, hospitalization rate, and social intervention effectiveness (masking, distancing, and mobility) are constant. However, the one certainty with the COVID-19 pandemic is that these parameters change over time, as well as vary across counties and states. In fact, the rate of spread over region, hospitalization rate, hospital length of stay and mortality rate, the proportion of the population that is susceptible, test positivity rate, and social behaviors can all change significantly over time. Thus, the quantification of uncertainty becomes critical in making meaningful and accurate forecasts of the future. Bayesian approaches are a natural way to fully represent this uncertainty in mathematical models and have become particularly popular in physics and engineering models. The explicit integration time varying parameters and uncertainty quantification into a hierarchical Bayesian forecast model differentiates the Mayo COVID-19 model from other forecasting models. By accounting for all sources of uncertainty in both parameter estimation as well as future trends with a Bayesian approach, the Mayo COVID-19 model accurately forecasts future cases and hospitalizations, as well as the degree of uncertainty. This approach has been remarkably accurate and a linchpin in Mayo Clinic's response to managing the COVID-19 pandemic. The model accurately predicted timing and extent of the summer and fall surges at Mayo Clinic sites, allowing hospital leadership to manage resources effectively to provide a successful pandemic response. This model has also proven to be very useful to the state of Minnesota to help guide difficult policy decisions.

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

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.

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

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 (preprint)

In 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 (preprint)

Importance: Passive 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. Objective: To explore potential signals of efficacy of COVID-19 convalescent plasma. Design: Open-label, Expanded Access Program (EAP) for the treatment of COVID-19 patients with human convalescent plasma. Setting: Multicenter, including 2,807 acute care facilities in the US and territories. Participants: Adult 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. Intervention: Transfusion 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 Measures: Seven and thirty-day mortality. Results: The 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 Relevance: The 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 Registration: ClinicalTrials.gov Identifier: NCT04338360

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

To determine the effect of COVID-19 convalescent plasma on mortality, we aggregated patient outcome data from randomized clinical trials, matched control, and case-series studies. Fixed-effects analyses demontrated that hospitalized COVID-19 patients transfused with convalescent plasma exhibited a a57% reduction in mortality rate (13%) compared to matched-patients receiving standard treatments (25%; 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.