Patients
The cohort consists of 3082 patients from 680 acute care facilities in the United States (Figure 1). Table 1 shows the most important characteristics of the patients, stratified into three groups according to anti-SARS-CoV-2 IgG antibody levels (based on signal-to-cut-off ratios). Overall, 61% of patients were male, 23% were black, 37% were Hispanic, 69% were younger than 70 years, and two-thirds had transfusions prior to invasive mechanical ventilation. The mean number of patients per site was 2 (interquartile range, 1 to 6). The maximum number of patients from any site was 59. As shown in Table 1, the three groups (patients receiving plasma transfusions with high, medium and low IgG antibody levels) were generally similar in 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 (which were both variables included in the adjustment models) were lower in the high-titer group than in the other two groups.
Primary outcome
Models of the relationship 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 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% BI, 0.61 to 0.93) (Table 2). Additional analyzes with adjustment for demographic characteristics of patients (age, weight status, and race) and clinical characteristics (receiving invasive mechanical ventilation, use of concomitant therapy, and hypoxemia) were performed to evaluate the overall effect of the anti-SARS-CoV. 2 IgG antibody level at risk of death within 30 days after transfusion (Table S1 in the Supplementary Appendix). The custom models (as defined in Table 2) generally showed a similar association – a lower relative risk of death among patients receiving plasma transfusions with high anti-SARS-CoV-2 IgG antibody levels (model 2, relative risk, 0.79 [95% CI, 0.65 to 0.96], a 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 received no mechanical ventilation and who received a recovery plasma, according to Anti-SARS-CoV-2 IgG level.
In the group of 3082 patients, 2014 patients did not receive mechanical ventilation before transfusion. Table 3 shows the most important characteristics of the patient of the subgroup of patients who did not receive mechanical ventilation stratified according to anti-SARS-CoV-2 IgG antibody levels. In the subgroup of patients who did not receive mechanical ventilation, death occurred within 30 days after plasma transfusion in 81 of 365 patients (22.2%; 95% AI, 18.2 to 26.7) in the low- titer group, 251 of 1297 patients (19.4%; 95% GI, 17.3 to 21.6) in the medium titer group and 50 of 352 patients (14.2%; 95% GI, 10.9 to 18.2) in the high-titer group; Table S4 shows these results in the subgroup of patients who received mechanical ventilation. In the subgroup of patients who received mechanical ventilation, death occurred within 30 days after plasma transfusion in 80 of 183 patients (43.7%; 95% AI, 36.7 to 51.0) in the low-titer group. , 277 of 666 patients (41.6%) 95% GI, 37.9 to 45.4) in the medium titer group, and 64 of 158 patients (40.5; 95% GI, 33.2 to 48 , 3) in the high-titer group. In both subgroups, the characteristics of the patients were well balanced in the three antibody titer groups.
In the fully adjusted relative risk regression model, the lower risk of death within 30 days after plasma transfusion was observed in the high-titer group than in the low-titer group among patients who did not receive mechanical ventilation before transfusion (relative risk, 0.66; 95% GI, 0.48 to 0.91). No effect on mortality was observed among patients who received mechanical ventilation before transfusion (relative risk, 1.02; 95% BI, 0.78 to 1.32).
Table S2 shows relative risk regression with or without complete adjustment for patient demographic characteristics, anti-SARS-CoV-2 IgG antibody levels, clinical characteristics, and study period, including all three models (the baseline model, model 2, and model 3). , for the subgroup of patients who did not receive mechanical ventilation. Table S3 shows relative risk regression for the subgroup of patients who received mechanical ventilation.
Relative risk of death within 30 days after recovery of plasma transfer.
Forest plots of the relative risks of death associated with medium at low antibody levels (panel A) and high versus low antibody levels (panel B) are shown. The subgroups are 12 mutually exclusive categories of the study period in 2020, patient age, and ventilator support in patients who received recovery plasma transfusions. The estimated relative risk of death among patients receiving a recovery plasma with IgG signal-to-cut-off rates in the range of 4.62 to 18.45 (medium titer) or more than 18.45 (high titer) is shown. compared to the relative risks among those who received plasma with IgG signal-to-cut-off ratios below 4.62 (low titer). The composite estimates of all the subgroups are based on the Mantel – Haenszel estimator. Table S5 gives the sample sizes and the number of deaths in each subgroup. 𝙸 measure indicates 95% confidence intervals.
These findings are further supported by a stratified data analytics approach that provides direct analytical control for the key variables associated with the risk of death (age, receipt of invasive mechanical ventilation, and study period) (Figure 2). The combined (or overall) relative risk of death among all patients within 30 days after plasma transfusion in the high-titer group compared to the low-titer group was 0.80 (95% CI, 0.65 up to 0.97)Figure 2). Figure S1 shows the risk of death within 7 days after transfusion of recovery plasma, as determined with this stratified data analytics approach.
Exploratory analyzes
Among patients receiving mechanical ventilation prior to transfusion, the mean (± SD) number of days between the diagnosis of Covid-19 and the transfusion of recovery plasma was 10.0 ± 7.7; it was almost double the mean number of days among patients who did not receive mechanical ventilation (5.4 ± 4.8). The unadjusted mortality rate within 30 days after transfusion was lower among patients who received a transfusion within 3 days after receiving a diagnosis of Covid-19 (score, 22.2%; 95% CI, 19.9 to 24, 8) as among those who received a transfusion 4 or more days after receiving a diagnosis of Covid-19 (estimate of point, 29.5%; 95% BI, 27.6 to 31.6). In model 3, replacing ventilation status with a binary classification of days to transfusion resulted in a relative death risk of 1.18 (95% AI, 1.04 to 1.35) among patients undergoing 4 or more days after receiving the diagnosis received a transfusion. This effect size was lower than that observed in patients who had previously received mechanical ventilation in model 3 (relative risk, 2.16; 95% BI, 1.90 to 2.46).
The trained gradient-enhancing machine was used to estimate the relationship between key variables associated with the risk of death within 30 days after plasma transfusion and mortality at 30 days. Two methods were used to investigate how this machine learning technique connects the key variables with the mortality predictions.
In the first method, a plot of variable importance was generated for each variable included in the model (Fig. S2). The “importance” of the variable is the relative amount with which it improves the prediction, both in terms of location in the decision trees (where more observations are classified higher in the decision tree) and in the number of times it is used in the collection of trees. The primary variables associated with the 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 varying importance.
The second method used to investigate the relationship between a given variable and the prediction of mortality was through a partial dependency plot. The partial dependence graph shows that anti-SARS-CoV-2 IgG antibody levels after adjustment for all other variables included in the model maintained an inverse relationship with the risk of death. Figure S3 shows similar partial dependency diagrams for the primary analysis model in which the antibody levels were treated as a continuous variable using a natural spline with four evenly distributed nodes. In this model, the partial dependency diagram for the overall sample is in line with the pattern observed in the gradient-enhancing machine model. The inverse association with antibody levels was again observed in the patients who did not have mechanical ventilation, and there was a general lack of a clear association in these patients.