Study patients, design, and data collection

The present study prospectively included all consecutive patients presenting with sepsis or septic shock on admission to the internistic ICU at the University Medical Center Mannheim, Germany, from June 2019 to January 2021 as recently published [15]. The presence of sepsis and septic shock, as well as important laboratory data, sepsis-related scores, hemodynamic measurements, ventilation parameters were assessed on disease onset (i.e., day 1), as well as on day 2, 3, 5, 7, and 10. Further documented data contained baseline characteristics, prior medical history, length of index hospital stay, data derived from imaging diagnostics, as well as pharmacological therapies. Documentation of source data was performed by intensivists and ICU nurses during routine clinical care.

The present study derived from an analysis of the “Mannheim Registry for Sepsis and Septic Shock” (MARSS-registry), which represents a prospective single-center registry including consecutive patients presenting with sepsis or septic shock, who were acutely admitted to the ICU for internal medicine of the University Medical Center Mannheim (UMM), Germany (clinicaltrials.gov identifier: NCT05231720). The registry was carried out according to the principles of the declaration of Helsinki and was approved by the medical ethics committee II of the Medical Faculty Mannheim, University of Heidelberg, Germany.

Inclusion and exclusion criteria, study endpoints

For the present study, all consecutive patients with sepsis and septic shock were included. Patients without CRP measurement on day 1 were excluded from the present study. No further exclusion criteria were applied. The diagnosis of sepsis and septic shock was determined according to the “Third International Consensus Definition for Sepsis and Septic Shock” (i.e., sepsis-3) [6]. Accordingly, sepsis was defined as life-threatening organ dysfunction, caused by a dysregulated host response to infection. Organ dysfunction is defined as an increase of ≥ 2 in the Sequential Organ Failure Assessment (SOFA) score. Septic shock was defined as persistent hypotension, despite adequate volume resuscitation, requiring vasopressors to maintain a mean arterial pressure (MAP) ≥ 65 mm Hg and a lactate ≥ 2 mmol/l [6].

All-cause mortality at 30 days was documented using our electronic hospital information system and by directly contacting state resident registration offices (‘bureau of mortality statistics’). Identification of patients was verified by place of name, surname, day of birth, and registered living address. No patient was lost to follow-up with regard all-cause mortality at 30 days.

Risk stratification

Firstly, the diagnostic and prognostic value of the CRP and PCT was investigated within the entire study cohort. Thereafter, the patients were stratified for initial sepsis and initial septic shock.

To investigate the prognostic role of the CRP and PCT stratified for dynamic disease progression and clinical improvement, the study group was divided into the following groups: (group 1) patients with initial sepsis without progression to septic shock according to current international guidelines [6]; (group 2) patients with initial sepsis with progression to septic shock; (group 3) patients with initial septic shock with clinical improvement to sepsis without shock; (group 4) patients with initial septic shock without clinical improvement. For this sub-analysis, patients were re-classified to sepsis without shock and septic shock according to the sepsis-3 criteria on the analyzed ICU treatment days (i.e., on days 1, 2, 3, 5, 7, and 10).

Statistical methods

Quantitative data is presented as mean ± standard error of mean (SEM), median, and interquartile range (IQR), and ranges depending on the distribution of the data. They were compared using the Student’s t-test for normally distributed data or the Mann–Whitney U test for nonparametric data. Deviations from a Gaussian distribution were tested by the Kolmogorov–Smirnov test. Qualitative data is presented as absolute and relative frequencies and was compared using the Chi-square test or the Fisher’s exact test, as appropriate. Box plots for CRP and PCT were created for the comparisons of patients with sepsis and septic shock during the first week of sepsis on days 1, 3, 5, 7, and 10. Spearman’s rank correlation for nonparametric data was used to test the association of the CRP and PCT with medical and laboratory parameters on day 1.

Diagnostic performance of CRP and PCT

C-statistics were applied with calculation of the receiver operating characteristic (ROC) and the corresponding area under the curve (AUC) within the entire cohort to assess the discriminative performance of the CRP and PCT with regard to the diagnosis of septic shock and sepsis at days 1, 3, 5, 7, and 10. Thereafter, the diagnostic accuracy of CRP and PCT with regard to blood-culture confirmed sepsis was tested. AUCs for the diagnostic performance were compared by the method of Hanley and McNeil [16].

Prognostic performance of CRP and PCT

C-statistics were applied with calculation of ROC and the corresponding AUC within the entire cohort at days 1, 3, 5, 7, and 10 with regard to the 30-day all-cause mortality. AUCs for prognostic performance were compared by the method of Hanley and McNeil [16].

Kaplan–Meier analyses according to the median CRP and PCT levels were performed within the entire study cohort, as well as separated by clinical improvement or impairment (i.e., groups 1–4). Univariable hazard ratios (HR) were given together with 95% confidence intervals.

Results of all statistical tests were considered significant for p ≤ 0.05. SPSS (Version 25, IBM, Armonk, New York) and GraphPad Prism (Version 9, GraphPad Software, San Diego, California) were used for statistics.