TNF-related apoptosis-inducing ligand, interferon gamma-induced protein 10, and C-reactive protein in predicting the progression of SARS-CoV-2 infection: a prospective cohort study

Abstract

Background: Early prognostication of COVID-19 severity will potentially improve patient care. Biomarkers, such as TNF-related apoptosis-inducing ligand (TRAIL), interferon gamma-induced protein 10 (IP-10), and C-reactive protein (CRP), might represent possible tools for point-of-care testing and severity prediction.

Methods: In this prospective cohort study, we analyzed serum levels of TRAIL, IP-10, and CRP in patients with COVID-19, compared them with control subjects, and investigated the association with disease severity.

Results: A total of 899 measurements were performed in 132 patients (mean age 64 years, 40.2% females). Among patients with COVID-19, TRAIL levels were lower (49.5 vs 87 pg/ml, P = 0.0142), whereas IP-10 and CRP showed higher levels (667.5 vs 127 pg/ml, P <0.001; 75.3 vs 1.6 mg/l, P <0.001) than healthy controls. TRAIL yielded an inverse correlation with length of hospital and intensive care unit (ICU) stay, Simplified Acute Physiology Score II, and National Early Warning Score, and IP-10 showed a positive correlation with disease severity. Multivariable regression revealed that obesity (adjusted odds ratio [aOR] 5.434, 95% confidence interval [CI] 1.005-29.38), CRP (aOR 1.014, 95% CI 1.002-1.027), and peak IP-10 (aOR 1.001, 95% CI 1.00-1.002) were independent predictors of in-ICU mortality.

Conclusions: We demonstrated a correlation between COVID-19 severity and TRAIL, IP-10, and CRP. Multivariable regression showed a role for IP-10 in predicting unfavourable outcomes, such as in-ICU mortality.

Trial registration: Clinicaltrials.gov, NCT04655521.

Keywords: Biomarkers; COVID-19; CRP; Host response; IP-10; Point-of-care testing; Severity prediction; TRAIL.

Figure 1

Flow diagram of the DIRECTOR study, conducted in Saarland, Germany (2020/2021); study population comprising SARS-CoV-2-positive patients only.

Figure 2

Differential expression of biomarkers between non-severe and severe COVID-19. Comparisons of (A) first TRAIL measurements, (B) first IP-10 measurements, and (C) first CRP measurements between patients who were admitted to the ICU (severe COVID-19, n = 47) and patients who remained in the NCU (Non-ICU = non-severe COVID-19, n = 85). Further comparisons (D-F) regarding patients requiring mechanical ventilation (MV, n = 29) and patients who did not (no MV, n = 103). The black line denotes the median of each group. The box identifies values between 25 and 75 percentiles, whereas the whiskers indicate minimal and maximal serum levels. P-values are defined as follows: ns: nonsignificant, *: P ≤0.05, **: P ≤0.01, ***: P ≤0.001. CRP: C reactive protein; ICU: intensive care unit; IP-10: interferon gamma-induced protein 10; TRAIL: TNF-related apoptosis-inducing ligand.

Figure 3

Correlation of biomarkers with SAPS II score. Correlation of all (A) TRAIL and (B) IP-10 measurements conducted in the ICU (n = 340) with the Simplified Acute Physiology II score. Significance levels, Spearman correlation coefficients (r), and simple linear regression lines are shown. P-values are defined as follows: ns: nonsignificant, *: P ≤0.05, **: P ≤0.01, ***: P ≤0.001. ICU: intensive care unit; IP-10: interferon gamma-induced protein 10; SAPS II: Simplified Acute Physiology Score II; TRAIL: TNF-related apoptosis-inducing ligand.

Figure 4

Differential expression of biomarkers between survivors of COVID-19 and in the ICU deceased patients with COVID-19. Comparisons of (A) minimal TRAIL levels and (B) maximal IP-10 levels between survivors of COVID-19 (NCU n = 77, ICU n = 34) and later in the ICU deceased patients with COVID-19 (n = 13). The black line denotes the median of each group. The box identifies values between 25 and 75 percentiles, whereas the whiskers indicate minimal and maximal serum levels. P-values are defined as follows: ns: nonsignificant, *: P ≤0.05, **: P ≤0.01, ***: P ≤0.001. ICU: intensive care unit; IP-10: interferon gamma-induced protein 10; NCU: normal care unit; TRAIL: TNF-related apoptosis-inducing ligand.

Figure 5

Correlation of TRAIL with NEWS-Score on admission. (A) Correlation of the New Early Warning Score of patients with COVID-19 presenting to the hospital's emergency department with initial TRAIL measurements conducted less than 24 hours after admission (n = 50). Significance level, Spearman correlation coefficient (r), and simple linear regression line are shown. (B) Comparison of initial TRAIL levels (measurements conducted less than 24 hours after admission) between patients presenting to the emergency department with a New Early Warning Score lower than 5 (n = 27) and patients with a New Early Warning Score of five or higher (n = 23). The black line denotes the median of each group. The box identifies values between 25 and 75 percentiles, whereas the whiskers indicate minimal and maximal serum levels. P-values are defined as follows: ns: nonsignificant, *: P ≤0.05, **: P ≤0.01, ***: P ≤0.001. ICU: intensive care unit; NEWS: New Early Warning Score; TRAIL: TNF-related apoptosis-inducing ligand.

Figure 6

Kaplain-Meier analyses of (A) the relation between initial TRAIL with cut-off 40 pg/ml for the outcome variable mechanical ventilation and (B) the relation between maximal IP-10 cut-off 3000 pg/ml and death in the ICU (maximum set at 100 days). ICU: intensive care unit; IP-10: interferon gamma-induced protein 10; MV: mechanical ventilation; TRAIL: TNF-related apoptosis-inducing ligand.