The long Pentraxin PTX3 serves as an early predictive biomarker of co-infections in COVID-19

Abstract

Background: COVID-19 clinical course is highly variable and secondary infections contribute to COVID-19 complexity. Early detection of secondary infections is clinically relevant for patient outcome. Procalcitonin (PCT) and C-reactive protein (CRP) are the most used biomarkers of infections. Pentraxin 3 (PTX3) is an acute phase protein with promising performance as early biomarker in infections. In patients with COVID-19, PTX3 plasma concentrations at hospital admission are independent predictor of poor outcome. In this study, we assessed whether PTX3 contributes to early identification of co-infections during the course of COVID-19.

Methods: We analyzed PTX3 levels in patients affected by COVID-19 with (n = 101) or without (n = 179) community or hospital-acquired fungal or bacterial secondary infections (CAIs or HAIs).

Findings: PTX3 plasma concentrations at diagnosis of CAI or HAI were significantly higher than those in patients without secondary infections. Compared to PCT and CRP, the increase of PTX3 plasma levels was associated with the highest hazard ratio for CAIs and HAIs (aHR 11.68 and 24.90). In multivariable Cox regression analysis, PTX3 was also the most significant predictor of 28-days mortality or intensive care unit admission of patients with potential co-infections, faring more pronounced than CRP and PCT.

Interpretation: PTX3 is a promising predictive biomarker for early identification and risk stratification of patients with COVID-19 and co-infections.

Funding: Dolce & Gabbana fashion house donation; Ministero della Salute for COVID-19; EU funding within the MUR PNRR Extended Partnership initiative on Emerging Infectious Diseases (Project no. PE00000007, INF-ACT) and MUR PNRR Italian network of excellence for advanced diagnosis (Project no. PNC-E3-2022-23683266 PNC-HLS-DA); EU MSCA (project CORVOS 860044).

Keywords: Biomarker; COVID-19; Community-acquired infections; Hospital-acquired infections; PTX3.

Fig. 1

Flow of patients in the study. Community-acquired infection (CAI); hospital-acquired infection (HAI).

Fig. 2

PTX3 plasma concentration in patients affected by COVID-19 with secondary infections. (a–f) PTX3, CRP and PCT plasma concentration at the time of co-infection diagnosis in patients affected by COVID-19 with CAIs (n = 31) (a-c-e) and HAIs (n = 70) (b-d-f) and their timing-related controls (n = 104 and 75 respectively). (g–h) ROC-analysis of PTX3, CRP and PCT for the identification of CAI (g) or HAI (h). a–f: Median with interquartile range are shown. Statistical significance was assessed with Wilcoxon-Mann-Whitney test. ∗: P < 0.05; ∗∗: P < 0.01; ∗∗∗∗: P < 0.0001.

Fig. 3

Modulation of inflammatory markers during hospitalization and at the co-infection in patients affected by COVID-19 with HAIs. (a–c) PTX3 (a), CRP (b) and PCT (c) plasma concentration in patients with HAIs at admission, co-infection, an intermediate time point between these two, specific for each patient, and at discharge or death. Admission, n = 62-65-64; Intermediate, n = 50-54-53; Co-infection, n = 70-68-68; Discharge, n = 37-37-35; Death, n = 23-24-25, for PTX3, CRP and PCT, respectively. Median and interquartile ranges are shown. Statistical significance was assessed by Kruskal–Wallis test with Dunn's multiple comparison test. ∗∗P < 0.01; ∗∗∗P < 0.001; ∗∗∗∗P < 0.0001. (d–f) PTX3 (d), CRP (e) and PCT (f) plasma concentrations in patients with COVID-19 and HAIs in the days preceding and following the microbiologic test. Mean and standard error of the mean (SEM) are shown. The number of values for each time-point is reported in the graphs. The vertical black dotted line shows the day of the microbiological test. The red horizontal dotted lines show the normal plasma concentration of PTX3 (d), the highest concentration of the range for moderate elevation for CRP (e), and the threshold for an infection for PCT (f). Statistical significance was assessed by Kruskal–Wallis test with Dunn's multiple comparison test comparing every time-points vs the time-point −6/−5.

Fig. 4

PTX3 plasma concentration in patients with COVID-19 divided by the site and type of secondary infection. (a) PTX3 plasma concentration in patients affected by COVID-19 with secondary infections at the time of co-infection and divided by site of infections (BSI, n = 35; UTI, n = 14; Pneumonia or Sepsis, n = 51) and their related controls (n = 179). (b) PTX3 plasma concentrations shown in a, analyzed separately in CAIs and HAIs (CAI: BSI, n = 11; UTI, n = 4; Pneumonia or Sepsis, n = 15; COVID-19 controls n = 104; and HAI: BSI, n = 24; UTI, n = 10; Pneumonia or Sepsis, n = 36; COVID-19 controls, n = 75). Patients with sepsis are shown in red. (c) PTX3 plasma concentration in patients with COVID-19 and secondary infections divided by type of pathogen (Gram-bacteria, n = 40; Gram + bacteria, n = 30, fungi, n = 5) and their related controls (n = 179). Median and interquartile ranges are shown. Statistical significance was assessed by Kruskal–Wallis test with Dunn's multiple comparison test. ∗P < 0.05; ∗∗P < 0.01; ∗∗∗P < 0.001; ∗∗∗∗P < 0.0001.

Fig. 5

Prognostic value of PTX3 in patients with COVID-19 and secondary infections. (a) PTX3 plasma concentration at hospital admission in the total cohort of patients stratified according to the outcome (survivors/non-ICU admission [positive outcome] n = 108; non survivors/ICU admission [adverse outcome] n = 86). Median with interquartile range is shown. Statistical significance was assessed with Wilcoxon-Mann-Whitney test. ∗∗∗∗: P < 0.0001. (b–c) PTX3 plasma concentration at hospital admission in patients with COVID-19 and CAIs divided by adverse outcome (COVID-19: positive outcome n = 87; adverse outcome n = 17; COVID-19 + CAIs: positive outcome n = 15; adverse outcome n = 16) (b); and HAIs at co-infection diagnosis (COVID-19: positive outcome n = 49; adverse outcome n = 26; COVID-19 + HAIs: positive outcome n = 9; adverse outcome n = 61) (c). b, c: Median with interquartile range are shown. Statistical significance was assessed with Kruskal–Wallis test (∗P < 0.05; ∗∗P < 0.01) and for patients with HAI by Mann–Whitney test ($ P < 0.05). (d, e) ROC-analysis of PTX3, CRP and PCT for the identification of adverse outcome (Death or ICU admission) in patients with COVID-19 and CAI (d) or HAI (e) and their related controls.

Fig. 6

Kaplan-Meir analysis of adverse events in patients with COVID-19 and secondary infections. (a, b, c) Kaplan-Meir curves by levels of PTX3 (a), CRP (b) and PCT (c) (high, H or low, L) (cut-off based on the ROC analysis reported in Fig. 5d) in patients with COVID-19 and CAIs and in their control patients with COVID-19. (d, e, f) Kaplan-Meir curves by levels of PTX3 (d), CRP (e) and PCT (f) (cut-off based on the ROC analysis reported in Fig. 5e) in patients with COVID-19 and HAIs. The numbers below the plot indicate patients at risk in time in the two or four groups.