Patients
The cohort consisted of 3082 patients from 680 acute care facilities across the United States (Figure 1). Table 1 shows key characteristics of the patients, stratified into three groups according to anti–SARS-CoV-2 IgG antibody levels (based on signal-to-cutoff ratios). Overall, 61% of the patients were men, 23% were Black, 37% were Hispanic, 69% were younger than 70 years of age, and two thirds had received transfusions before invasive mechanical ventilation. The median number of patients per site was 2 (interquartile range, 1 to 6). The maximum number of patients from any single site was 59. As shown in Table 1, the three groups (patients who received plasma transfusions with high, medium, and low IgG antibody levels) were generally similar in terms of demographic characteristics, risk factors associated with severe Covid-19, and concomitant use of therapeutic agents for Covid-19. The percentages of patients with hypoxemia and concomitant use of hydroxychloroquine (both of which were variables that were included in adjustment models) were lower in the high-titer group than in the other two groups.
Primary Outcome
Models of the Association between Anti–SARS-CoV-2 Antibody Levels in Transfused Plasma and the Risk of Death.
Death within 30 days after plasma transfusion occurred in 26.9% of all the patients (830 of 3082 patients; 95% confidence interval [CI], 25.4 to 28.5). This primary-outcome event occurred in 29.6% (166 of 561 patients) in the low-titer group, 27.4% (549 of 2006 patients) in the medium-titer group, and 22.3% (115 of 515 patients) in the high-titer group. Patients in the high-titer group had a lower relative risk of death within 30 days after transfusion than patients in the low-titer group (relative risk, 0.75; 95% CI, 0.61 to 0.93) (Table 2). Additional analyses with adjustment for patient demographic characteristics (age, weight status, and race) and clinical characteristics (receipt of invasive mechanical ventilation, use of concomitant therapeutics, and hypoxemia) were conducted to evaluate the overall effect of the anti–SARS-CoV-2 IgG antibody level on the risk of death within 30 days after transfusion (Table S1 in the Supplementary Appendix). The adjusted models (as defined in Table 2) generally showed a similar association — a lower relative risk of death among patients who received plasma transfusions with high anti–SARS-CoV-2 IgG antibody levels (model 2, relative risk, 0.79 [95% CI, 0.65 to 0.96], and model 3 [with additional adjustment], relative risk, 0.82 [95% CI, 0.67 to 1.00]) (Table 2). The findings of the sensitivity analysis in which patients were excluded at discharge were qualitatively similar to each of these findings.
Subgroup Analysis
Characteristics of Patients with Covid-19 Who Were Not Receiving Mechanical Ventilation and Who Received Convalescent Plasma, According to Anti–SARS-CoV-2 IgG Level.
In the cohort of 3082 patients, 2014 patients did not receive mechanical ventilation before transfusion. Table 3 shows key patient characteristics of the subgroup of patients who were not receiving mechanical ventilation, stratified according to anti–SARS-CoV-2 IgG antibody levels. In the subgroup of patients who were not receiving mechanical ventilation, death within 30 days after plasma transfusion occurred in 81 of 365 patients (22.2%; 95% CI, 18.2 to 26.7) in the low-titer group, 251 of 1297 patients (19.4%; 95% CI, 17.3 to 21.6) in the medium-titer group, and 50 of 352 patients (14.2%; 95% CI, 10.9 to 18.2) in the high-titer group; Table S4 shows these results in the subgroup of patients who were receiving mechanical ventilation. In the subgroup of patients who were receiving mechanical ventilation, death within 30 days after plasma transfusion occurred in 80 of 183 patients (43.7%; 95% CI, 36.7 to 51.0) in the low-titer group, 277 of 666 patients (41.6%; 95% CI, 37.9 to 45.4) in the medium-titer group, and 64 of 158 patients (40.5; 95% CI, 33.2 to 48.3) in the high-titer group. In both subgroups, the characteristics of the patients were well balanced across the three antibody-titer groups.
In the fully adjusted relative risk regression model, the lower risk of death within 30 days after plasma transfusion in the high-titer group than in the low-titer group was observed among patients who were not receiving mechanical ventilation before transfusion (relative risk, 0.66; 95% CI, 0.48 to 0.91). No effect on mortality was observed among patients who received mechanical ventilation before transfusion (relative risk, 1.02; 95% CI, 0.78 to 1.32).
Table S2 shows relative-risk regression with or without full adjustment for patient demographic characteristics, anti–SARS-CoV-2 IgG antibody levels, clinical characteristics, and study time period, including all three models (the base model, model 2, and model 3), for the subgroup of patients who were not receiving mechanical ventilation. Table S3 shows relative-risk regression for the subgroup of patients who were receiving mechanical ventilation.
Relative Risk of Death within 30 Days after Convalescent Plasma Transfusion.
Forest plots of the relative risks of death associated with medium versus low antibody levels (Panel A) and high versus low antibody levels (Panel B) are shown. The subgroups are 12 mutually exclusive categories of the time period of the study in 2020, patient age, and ventilator support in patients who received transfusions of convalescent plasma. Shown are the estimated relative risks of death among patients who received convalescent plasma with IgG signal-to-cutoff ratios in the range of 4.62 to 18.45 (medium titer) or more than 18.45 (high titer), as compared with the relative risks among those who received plasma with IgG signal-to-cutoff ratios below 4.62 (low titer). The pooled estimates from all the subgroups are based on the Mantel–Haenszel estimator. Table S5 provides the sample sizes and number of deaths in each subgroup. 𝙸 bars indicate 95% confidence intervals.
These findings were further supported by a stratified-data analytic approach that provided direct analytic control for the key variables associated with the risk of death (age, receipt of invasive mechanical ventilation, and study time period) (Figure 2). The pooled (or common) relative risk of death among all the patients within 30 days after plasma transfusion in the high-titer group, as compared with the low-titer group, was 0.80 (95% CI, 0.65 to 0.97) (Figure 2). Figure S1 shows the risk of death within 7 days after transfusion of convalescent plasma, as determined with this stratified data analytic approach.
Exploratory Analyses
Among patients who received mechanical ventilation before transfusion, the mean (±SD) number of days between the diagnosis of Covid-19 and the transfusion of convalescent plasma was 10.0±7.7; this was nearly double the mean number of days among patients who were not receiving mechanical ventilation (5.4±4.8). The unadjusted mortality within 30 days after transfusion was lower among patients who received a transfusion within 3 days after receiving a diagnosis of Covid-19 (point estimate, 22.2%; 95% CI, 19.9 to 24.8) than among those who received a transfusion 4 or more days after receiving a diagnosis of Covid-19 (point estimate, 29.5%; 95% CI, 27.6 to 31.6). In model 3, the replacement of ventilation status with a binary classification of days to transfusion resulted in a relative risk of death of 1.18 (95% CI, 1.04 to 1.35) among patients who received a transfusion 4 or more days after receiving the diagnosis. This effect size was lower than that observed in patients who had previously received mechanical ventilation in model 3 (relative risk, 2.16; 95% CI, 1.90 to 2.46).
The trained gradient-boosting machine was used to estimate the relationship between key variables associated with risk of death within 30 days after plasma transfusion and mortality at 30 days. Two methods were used to explore how this machine-learning technique linked the key variables with the mortality predictions.
In the first method, a variable importance plot was generated for each variable included in the model (Fig. S2). The “importance” of the variable is the relative amount by which it improves the prediction, both in terms of location in the decision trees (where more observations are classified higher up in the decision tree) and in the number of times it is used in the collection of trees. The primary variables associated with a risk of death at 30 days were age; evidence of an advanced clinical course of Covid-19, such as the receipt of invasive mechanical ventilation and admission to an intensive care unit (ICU); and the anti–SARS-CoV-2 antibody level, in order of variable importance.
The second method used to explore the association between a given variable and prediction of mortality was by means of a partial dependence plot. The partial dependence plot shows that after adjustment for all other variables included in the model, anti–SARS-CoV-2 IgG antibody levels maintained an inverse relationship with the risk of death. Figure S3 shows similar partial dependence plots for the primary analysis model in which the antibody levels were treated as a continuous variable with the use of a natural spline with four evenly spaced knots. In this model, the partial dependence plot for the overall sample aligned closely with the pattern observed in the gradient-boosting machine model. The inverse relationship with antibody levels was again observed in the patients who were not receiving mechanical ventilation, and there was a general lack of a clear association in these patients.
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