Inhibitory Immune Checkpoint Molecule Expression in Clinical Sepsis Studies: A Systematic Review

Checkpoint inhibitors have been proposed for sepsis following reports of increased checkpoint molecule expression in septic patients. To determine whether clinical studies investigating checkpoint molecule expression provide strong evidence supporting trials of checkpoint inhibitors for sepsis.

PubMed, EMBASE, Scopus, Web of Science, inception through October 2019.

Studies comparing checkpoint molecule expression in septic patients versus healthy controls or critically ill nonseptic patients or in sepsis nonsurvivors versus survivors.

Two investigators extracted data and evaluated study quality.

Thirty-six studies were retrieved. Across 26 studies, compared with healthy controls, septic patients had significantly (p ≤ 0.05) increased CD4+ lymphocyte programmed death-1 and monocyte programmed death-ligand-1 expression in most studies. Other checkpoint molecule expressions were variable and studied less frequently. Across 11 studies, compared with critically ill nonseptic, septic patients had significantly increased checkpoint molecule expression in three or fewer studies. Septic patients had higher severity of illness scores, comorbidities, and mortality in three studies providing analysis. Across 12 studies, compared with septic survivors, nonsurvivors had significantly increased expression of any checkpoint molecule on any cell type in five or fewer studies. Of all 36 studies, none adjusted for nonseptic covariates reported to increase checkpoint molecule expression.

Although sepsis may increase some checkpoint molecule expression compared with healthy controls, the data are limited and inconsistent. Further, data from the more informative patient comparisons are potentially confounded by severity of illness. These clinical checkpoint molecule expression studies do not yet provide a strong rationale for trials of checkpoint inhibitor therapy for sepsis.