Evidence for Persistent Immune Suppression in Patients Who Develop Chronic Critical Illness After Sepsis

Abstract

Background: Many sepsis survivors develop chronic critical illness (CCI) and are assumed to be immunosuppressed, but there is limited clinical evidence to support this. We sought to determine whether the incidence of secondary infections and immunosuppressive biomarker profiles of patients with CCI differ from those with rapid recovery (RAP) after sepsis.

Methods: This prospective observational study evaluated 88 critically ill patients with sepsis and 20 healthy controls. Cohorts were defined based on clinical trajectory (early death, RAP, or CCI), whereas immunosuppression was clinically determined by the presence of a postsepsis secondary infection. Serial blood samples were collected for absolute lymphocyte counts (ALCs), monocytic human leukocyte antigen-DR (mHLA-DR) expression, and plasma-soluble programmed death-ligand 1 (sPD-L1) concentrations.

Results: Of the 88 patients with sepsis, 3 (3%) died within 14 days of sepsis onset, 50 (57%) experienced RAP, and 35 (40%) developed CCI. Compared with RAP patients, CCI patients exhibited a higher incidence and overall number of infections adjusted for hospital length of stay. ALC and mHLA-DR levels were dramatically reduced at the time of sepsis diagnosis when compared with healthy controls, whereas sPD-L1 concentrations were significantly elevated. There were no differences between RAP and CCI patients in ALC, sPD-L1, or mHLA-DR at the time of diagnosis or within 24 h after sepsis diagnosis. However, in contrast to the RAP group, CCI patients failed to exhibit any trend toward restoration of normal values of ALC, HLA-DR, and sPD-L1.

Conclusions: Septic patients demonstrate clinical and biological evidence to suggest they are immunosuppressed at the time of sepsis diagnosis. Those who develop CCI have a greater incidence of secondary infections and persistently aberrant markers of impaired host immunity, although measurements at the time of sepsis onset did not distinguish between subjects with RAP and CCI.

Figure 1. Flow Diagram Outlining Patient Enrollment and Classification

Figure 2. Incidence of Secondary Infections Over Time in Patients with Chronic Critical Illness (CCI) versus Rapid Recovery (RAP)

Kaplan-Meier curves show cumulative incidence of secondary infections in the CCI and RAP groups over a 60-day period.

Figure 3. Six Month Mortality Analysis in Patients with Chronic Critical Illness (CCI) versus Rapid Recovery (RAP)

The Kaplan-Meier curve demonstrates cumulative survival rate over 6 months in CCI versus RAP patients. Patients who have yet to reach 6 months after their initial sepsis event are censored and are denoted with tick marks.

Figure 4. Biomarkers of Immunosuppression Over Time in Patients with Chronic Critical Illness (CCI) versus Rapid Recovery (RAP)

Blood samples were collected at 0.5, 1, 4, 7, 14, 21, and 28 days after sepsis protocol onset from patients who developed sepsis in the surgical ICU and these patients were prospectively followed for development of CCI versus RAP. Absolute Lymphocyte counts (ALC) (panel A), HLA-DR expression on CD14⁺ monocytes (panel B), and plasma concentrations of sPD-L1 (panel C) were used to measure immune status in these patients. The biomarker means of CCI (▲) and RAP (●) patients are reported at each time point. Using general estimating equations with Poisson variance assumption and log link, fitted mean function lines were plotted for the CCI and RAP groups with 95% confidence interval bands (RAP designated in blue and CCI designated in red). The estimated differences in slopes between CCI and RAP groups over time were significant for ALC (p=0.036) and sPD-L1 (−0.03, p=0.004) at 0.05 level and for HLA-DR (p=0.069) at 0.1 level, indicating ALC and HLA-DR were increasing and sPD-L1 was decreasing over time faster for RAP group. Non-parametric rank tests were also performed to determine significant differences at individual times, which are denoted along the x-axis with an asterisk (*). For ALC, the normal range for healthy controls are reported according to our institution’s reference range. With regards to HLA-DR and sPD-L1, values from healthy controls are reported as the mean with standard error bands.

Figure 5. Biomarker Prediction Modeling for the Development of Chronic Critical Illness (CCI) and Secondary Infections

Odds ratios were derived using logistic regression models both individually and including all listed variables, simultaneously. All prediction models were created using data obtained 24 hours after sepsis management protocol onset. Receiver operating curves were constructed with the relative AUCs of each curve being reflected in the corresponding table. Aside from the absolute lymphocyte count (ALC), the other biomarkers (HLA-DR and sPD-L1) were relatively poor at predicting CCI and secondary infections. [Table: see text]

Figure 5. Biomarker Prediction Modeling for the Development of Chronic Critical Illness (CCI) and Secondary Infections

Odds ratios were derived using logistic regression models both individually and including all listed variables, simultaneously. All prediction models were created using data obtained 24 hours after sepsis management protocol onset. Receiver operating curves were constructed with the relative AUCs of each curve being reflected in the corresponding table. Aside from the absolute lymphocyte count (ALC), the other biomarkers (HLA-DR and sPD-L1) were relatively poor at predicting CCI and secondary infections. [Table: see text]