PD1 PDL1 CTLA4 BTLA 1
3 5 7 9 11 13
0
CD4 or CD3+
PD1 PDL1 CTLA4 BTLA 1
3 5 7 9 11 13
0
CD8+
PD1 PDL1
1 3 5 7 9 11 13
0
Monocytes
PD1 PDL1 BTLA
1 3 5 7 9 11 13
0
Soluble
PD1 PDL1 CTLA4 BTLA 1
3 5 7 9 11 13
0
CD4 or CD3+
PD1 PDL1 CTLA4 BTLA 1
3 5 7 9 11 13
0
CD8+
PD1 PDL1
1 3 5 7 9 11 13
0
Monocytes
PD1 PDL1 BTLA
1 3 5 7 9 11 13
0
Soluble
PD1 PDL1 CTLA4 BTLA 1
3 5 7 9 11 13
0
CD4 or CD3+
PD1 PDL1 CTLA4 BTLA 1
3 5 7 9 11 13
0
CD8+
PD1 PDL1
1 3 5 7 9 11 13
0
Monocytes
PD1 PDL1 BTLA
1 3 5 7 9 11 13
0
Soluble
Septic vs HC Septic vs CINS Septic NS vs S
CD3+ or CD4+ Lymphocytes
CD8+ Lymphocytes
Monocytes
Soluble
A. B. C.
D. E. F.
G. H. I.
J. K. L.
Number of studies with the indicated change in checkpoint molecule expression
Increase No difference Decrease ( ) Number of studies providing mean and variability (6) (2) (1) (3)
(4) (1) (0) (0)
(0) (0) (1)
(2) (4)
(3) (1) (1)
(0) (0)
(0) (0)
(2) (0) (2) (2) (1) (1)
(0) (2)
(2) (0)
(4) (0) (1) (2)
#
*
*
Number of studies
Supplementary Figure 2. Panels A to L show the number of studies reporting either a statistically significant increase (black bars), significant decrease (white bars), or no significant difference (gray bar) in the checkpoint molecule PD-1, PD-L1, CTLA-4, or BTLA on CD3+ or CD4+ lymphocytes, CD8+ lymphocytes or monocytes in studies that compared this expression in septic patients versus healthy control subject (Panels A, D, and G), septic versus critically ill non-septic patients (Panel B, E, and H), or septic non-survivors versus survivor (Panels C, F, and I). Panels J to L show similar results for soluble checkpoint molecule levels for these three compari- sons. Numbers in parentheses denote the number of studies which provided mean with variability data. For studies presenting CME as both cell frequency and MFI, or that presented CME on more than one day after presentation, if either measure was significantly different in septic versus control patients or in septic non-survivors versus survivors on any day measurements were made, the study was recorded as demonstrating a significant change (see methods).
†One study (32) reported no difference in %BTLA+ in septic vs HC, but decreased %BTLA+ in severe sepsis or septic shock vs HC, and increased BTLA MFI in septic vs HC, but no difference in BTLA MFI in severe sepsis or septic shock vs HC. This study received notation for both an increase and decrease.
*One study displayed the indicated change by cell frequency but there was no difference by MFI. Please see Supplementary tables for detailed results.