Development and Validation of a Treatment Benefit Index to Identify Hospitalized Patients With COVID-19 Who May Benefit From Convalescent Plasma

Abstract

Importance: Identifying which patients with COVID-19 are likely to benefit from COVID-19 convalescent plasma (CCP) treatment may have a large public health impact.

Objective: To develop an index for predicting the expected relative treatment benefit from CCP compared with treatment without CCP for patients hospitalized for COVID-19 using patients' baseline characteristics.

Design, setting, and participants: This prognostic study used data from the COMPILE study, ie, a meta-analysis of pooled individual patient data from 8 randomized clinical trials (RCTs) evaluating CCP vs control in adults hospitalized for COVID-19 who were not receiving mechanical ventilation at randomization. A combination of baseline characteristics, termed the treatment benefit index (TBI), was developed based on 2287 patients in COMPILE using a proportional odds model, with baseline characteristics selected via cross-validation. The TBI was externally validated on 4 external data sets: the Expanded Access Program (1896 participants), a study conducted under Emergency Use Authorization (210 participants), and 2 RCTs (with 80 and 309 participants).

Exposure: Receipt of CCP.

Main outcomes and measures: World Health Organization (WHO) 11-point ordinal COVID-19 clinical status scale and 2 derivatives of it (ie, WHO score of 7-10, indicating mechanical ventilation to death, and WHO score of 10, indicating death) at day 14 and day 28 after randomization. Day 14 WHO 11-point ordinal scale was used as the primary outcome to develop the TBI.

Results: A total of 2287 patients were included in the derivation cohort, with a mean (SD) age of 60.3 (15.2) years and 815 (35.6%) women. The TBI provided a continuous gradation of benefit, and, for clinical utility, it was operationalized into groups of expected large clinical benefit (B1; 629 participants in the derivation cohort [27.5%]), moderate benefit (B2; 953 [41.7%]), and potential harm or no benefit (B3; 705 [30.8%]). Patients with preexisting conditions (diabetes, cardiovascular and pulmonary diseases), with blood type A or AB, and at an early COVID-19 stage (low baseline WHO scores) were expected to benefit most, while those without preexisting conditions and at more advanced stages of COVID-19 could potentially be harmed. In the derivation cohort, odds ratios for worse outcome, where smaller odds ratios indicate larger benefit from CCP, were 0.69 (95% credible interval [CrI], 0.48-1.06) for B1, 0.82 (95% CrI, 0.61-1.11) for B2, and 1.58 (95% CrI, 1.14-2.17) for B3. Testing on 4 external datasets supported the validation of the derived TBIs.

Conclusions and relevance: The findings of this study suggest that the CCP TBI is a simple tool that can quantify the relative benefit from CCP treatment for an individual patient hospitalized with COVID-19 that can be used to guide treatment recommendations. The TBI precision medicine approach could be especially helpful in a pandemic.

Figure 1.. Odds Ratios of COVID-19 Convalescent Plasma (CCP) Efficacy and Expanded Treatment Benefit Index

For all 6 outcomes, odds ratios of CCP efficacy (vs control) are shown as a function of the expanded treatment benefit index developed on the outcome of day-14 ordinal World Health Organization (WHO) scale. The plotted odds ratios (ORs) were estimated from cumulative proportional odds models or logistic models, depending on the outcome. The regressors were treatment, spline-represented treatment benefit index, and spline-represented treatment benefit index × treatment interaction, not adjusted for any other covariates. ORs for CCP efficacy of less than 1 indicate better outcome with CCP treatment than control. The cut points distinguishing benefit levels B1, B2, and B3 were 0.20 and 0.37 and are the same for all panels. The solid curves represent the ORs from the model, and the dashed curves indicate the associated 95% bootstrap confidence bands. The ORs for the 3 benefit levels are estimated from the primary bayesian models used in the analysis of the main results.

Figure 2.. Time to Death and Discharge Within 28 Days in 3 Benefit Level Groups

Log-rank tests stratified for randomized clinical trials were used to compare COVID-19 Convalescent Plasma (CCP) and control for the mortality outcome. Gray competing risk test was used to compare CCP and control for the discharge outcome.

Figure 3.. Preexisting Health Status, Stage of COVID-19 Illness at Time of Treatment, and Benefit From COVID-19 Convalescent Plasma (CCP)

Patients in the upper left corner (A), who have high preexisting risk but are at an early stage of COVID-19, are expected to have large benefit from CCP treatment. Patients with high preexisting risk who are at an advanced stage of COVID-19 (upper-right corner; B) as well as patients with low preexisting risk who are at early stage of COVID-19 (lower-left corner; C) are expected to benefit less from CCP. Patients with low preexisting risk who are at an advanced stage of COVID-19 (lower-right corner; D) are not expected to benefit and might experience harm from CCP treatment. WHO indicates World Health Organization.

Figure 4.. Predicted Patient Status for 4 Sample Patients

All 4 hypothetical patients were aged 60 years and had blood type O. Patient A had high preexisting risk (ie, cardiovascular disease, diabetes, and pulmonary disease) and early-stage COVID, with a treatment benefit index score of 0.85 (benefit level B1); patient B, high preexisting risk and later-stage COVID-19, with a treatment benefit index score of 0.68 (benefit level B1); patient C, low preexisting risk and early-stage COVID-19, with a treatment benefit index score of 0.36 (benefit level B2); and patient D, low preexisting risk and late-stage COVID-19, with a treatment benefit score of 0.19 (benefit level B3). CCP indicates COVID-19 convalescent plasma; WHO, World Health Organization.