Irish Journal of Medical Science (1971 -) (2024) 193:457–468

https://doi.org/10.1007/s11845-023-03385-8

ORIGINAL ARTICLE

C‑reactive protein and procalcitonin during course of sepsis

and septic shock
Tobias Schupp1,2 · Kathrin Weidner1,2 · Jonas Rusnak1,2 · Schanas Jawhar1,2 · Jan Forner1,2 · Floriana Dulatahu1,2 ·
Jonas Dudda1,2 · Lea Marie Brück1,2 · Ursula Hoffmann1,2 · Thomas Bertsch3 · Ibrahim Akin1,2 · Michael Behnes1,2,4

Received: 15 September 2022 / Accepted: 20 April 2023 / Published online: 19 May 2023
© The Author(s) 2023

Abstract
Objective The study investigates the diagnostic and prognostic value of C-reactive protein (CRP) and procalcitonin (PCT)
in patients with sepsis and septic shock.
Background Limited data regarding the prognostic value of CRP and PCT during the course of sepsis or septic shock is available.
Methods Consecutive patients with sepsis and septic shock from 2019 to 2021 were included monocentrically. Blood
samples were retrieved from the day of disease onset (day 1), day 2, 3, 5, 7, and 10. Firstly, the diagnostic value of CRP and
PCT for the diagnosis of a septic shock, as well as for the discrimination of positive blood cultures, was tested. Secondly,
the prognostic value of the CRP and PCT was tested for 30-day all-cause mortality. Statistical analyses included univariable
t-tests, Spearman’s correlations, C-statistics, and Kaplan–Meier analyses.
Results A total of 349 patients were included, of which 56% had a sepsis and 44% a septic shock on day 1. The overall rate of
all-cause mortality at 30 days was 52%. With an area under the curve (AUC) of 0.861 on day 7 and 0.833 on day 10, the PCT
revealed a superior AUC than the CRP (AUC 0.440–0.652) with regard to the discrimination between patients with sepsis
and septic shock. In contrast, the prognostic AUCs for 30-day all-cause mortality were poor. Both higher CRP (HR = 0.999;
95% CI 0.998–1.001; p = 0.203) and PCT levels (HR = 0.998; 95% CI 0.993–1.003; p = 0.500) were not associated with the
risk of 30-day all-cause mortality. During the first 10 days of ICU treatment, both CRP and PCT declined irrespective of
clinical improvement or impairment.
Conclusion PCT was a reliable diagnostic tool for the diagnosis of septic shock compared to CRP. Both CRP and PCT were
shown to have poor predictive value with regard to 30-day all-cause mortality and were not associated with the risk of all-
cause mortality in patients admitted with sepsis or septic shock.

Keywords C-reactive protein · Mortality · Procalcitonin · Prognosis · Sepsis · Septic shock

Introduction
* Michael Behnes
[email protected] Sepsis represents a major reason for intensive care unit
(ICU) admission and is associated with high risk of mor-
1
Department of Cardiology, Angiology, Haemostaseology bidity and mortality [1]. During the past years, no signifi-
and Medical Intensive Care, Medical Faculty Mannheim,
University Medical Centre Mannheim, Heidelberg cant improvement of sepsis-related mortality was observed,
University, Heidelberg, Germany although many studies investigated the potential role of
2
European Center for AngioScience (ECAS), German novel biomarkers to improve the risk stratification of
Center for Cardiovascular Research (DZHK) Partner Site patients with sepsis and high risk of death [2–5]. Despite
Heidelberg/Mannheim, Mannheim, Germany the ongoing research to identify biomarkers or combinations
3
Institute of Clinical Chemistry, Laboratory Medicine of biomarkers with improved accuracy for the diagnosis of
and Transfusion Medicine, Nuremberg General Hospital, sepsis or septic shock, inflammatory markers are not yet
Paracelsus Medical University, Nuremberg, Germany included in the diagnosis-making of sepsis within the current
4
First Department of Medicine, University Medical sepsis guidelines [6].
Center Mannheim (UMM), Theodor‑Kutzer‑Ufer 1‑3,
68167 Mannheim, Germany

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458 Irish Journal of Medical Science (1971 -) (2024) 193:457–468

C-reactive protein (CRP), discovered in 1930, is a non- therapies. Documentation of source data was performed by
specific acute phase protein which may be increased up intensivists and ICU nurses during routine clinical care.
to 10,000-fold during acute responses to severe infection, The present study derived from an analysis of the “Man-
sepsis, or major tissue damage [7]. By activating cytotoxic nheim Registry for Sepsis and Septic Shock” (MARSS-
cascades, CRP is involved in the process of removing micro- registry), which represents a prospective single-center
organisms and necrotic tissue [8]. In clinic routine, CRP is registry including consecutive patients presenting with
frequently measured as a diagnostic tool for infection, as a sepsis or septic shock, who were acutely admitted to the
marker for disease severity, as well as for the assessment of ICU for internal medicine of the University Medical Center
the therapeutic response (i.e., following antibiotic therapy) Mannheim (UMM), Germany (clinicaltrials.gov identi-
[9]. Even in patients with cardiogenic shock, increasing CRP fier: NCT05231720). The registry was carried out accord-
was recently shown to indicate increased short-term mortality ing to the principles of the declaration of Helsinki and was
[10]. Within a meta-analysis including 9 studies and 1,368 approved by the medical ethics committee II of the Medical
patients, CRP was shown to have a moderate accuracy for Faculty Mannheim, University of Heidelberg, Germany.
the diagnosis of sepsis (area under the curve (AUC) = 0.73),
while the diagnostic accuracy of procalcitonin (PCT) was Inclusion and exclusion criteria, study endpoints
higher (AUC = 0.85) [11]. PCT is a serum peptide with yet
unknown function, however, PCT is commonly increased For the present study, all consecutive patients with sepsis
in patients with bacterial infection. Although the PCT was and septic shock were included. Patients without CRP meas-
demonstrated to be increased in patients with sepsis within urement on day 1 were excluded from the present study.
various studies, Tang et al. concluded that the PCT cannot No further exclusion criteria were applied. The diagnosis
differentiate sepsis from other causes of a systemic inflam- of sepsis and septic shock was determined according to the
matory response syndrome (SIRS) including 18 studies and “Third International Consensus Definition for Sepsis and
more than 2,000 patients [12]. Septic Shock” (i.e., sepsis-3) [6]. Accordingly, sepsis was
Whether CRP and PCT represent good predictors for the defined as life-threatening organ dysfunction, caused by a
severity of a sepsis, as well as the sepsis-related mortality dysregulated host response to infection. Organ dysfunction is
remains controversial [13, 14]. In 2004, our study group defined as an increase of ≥ 2 in the Sequential Organ Failure
suggested no prognostic impact of CRP and PCT measure- Assessment (SOFA) score. Septic shock was defined as per-
ment in patients with sepsis or septic shock, however, the sistent hypotension, despite adequate volume resuscitation,
prognostic role in the current sepsis-3 era needs further requiring vasopressors to maintain a mean arterial pressure
investigation [3]. Specifically, the role of the CRP and PCT (MAP) ≥ 65 mm Hg and a lactate ≥ 2 mmol/l [6].
during the course of a sepsis or septic shock, stratified by All-cause mortality at 30 days was documented using
disease progression or clinical improvement has not yet been our electronic hospital information system and by directly
investigated. Therefore, the present study comprehensively contacting state resident registration offices (‘bureau of mor-
investigates the diagnostic and prognostic value of the CRP tality statistics’). Identification of patients was verified by
compared to the PCT in patients admitted to an internistic place of name, surname, day of birth, and registered living
ICU with sepsis or septic shock. address. No patient was lost to follow-up with regard all-
cause mortality at 30 days.

Methods Risk stratification

Study patients, design, and data collection Firstly, the diagnostic and prognostic value of the CRP and
PCT was investigated within the entire study cohort. There-
The present study prospectively included all consecutive after, the patients were stratified for initial sepsis and initial
patients presenting with sepsis or septic shock on admission septic shock.
to the internistic ICU at the University Medical Center Man- To investigate the prognostic role of the CRP and
nheim, Germany, from June 2019 to January 2021 as recently PCT stratified for dynamic disease progression and clini-
published [15]. The presence of sepsis and septic shock, as cal improvement, the study group was divided into the
well as important laboratory data, sepsis-related scores, hemo- following groups: (group 1) patients with initial sepsis
dynamic measurements, ventilation parameters were assessed without progression to septic shock according to current
on disease onset (i.e., day 1), as well as on day 2, 3, 5, 7, and international guidelines [6]; (group 2) patients with initial
10. Further documented data contained baseline characteris- sepsis with progression to septic shock; (group 3) patients
tics, prior medical history, length of index hospital stay, data with initial septic shock with clinical improvement to sep-
derived from imaging diagnostics, as well as pharmacological sis without shock; (group 4) patients with initial septic

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Irish Journal of Medical Science (1971 -) (2024) 193:457–468 459

shock without clinical improvement. For this sub-analysis, and GraphPad Prism (Version 9, GraphPad Software, San
patients were re-classified to sepsis without shock and sep- Diego, California) were used for statistics.
tic shock according to the sepsis-3 criteria on the analyzed
ICU treatment days (i.e., on days 1, 2, 3, 5, 7, and 10).
Results

Statistical methods Study population

Quantitative data is presented as mean ± standard error of From a total of 361 consecutive patients with sepsis or
mean (SEM), median, and interquartile range (IQR), and septic shock, 12 patients without CRP measurement on
ranges depending on the distribution of the data. They were day 1 were excluded. The final study cohort comprised
compared using the Student’s t-test for normally distributed of 349 patients with sepsis or septic shock on admission.
data or the Mann–Whitney U test for nonparametric data. 56% of the patients presented with a sepsis and 44% with
Deviations from a Gaussian distribution were tested by the a septic shock on day 1. The median CRP level on day 1
Kolmogorov–Smirnov test. Qualitative data is presented as was 144 mg/l (IQR 83–220 mg/l). PCT was measured in
absolute and relative frequencies and was compared using 270 patients (77%) on day 1 (median PCT level 2.8 ng/
the Chi-square test or the Fisher’s exact test, as appropriate. ml (IQR 0.7–18.4 ng/ml)). As seen in Table 1, patients
Box plots for CRP and PCT were created for the compari- were median-aged at 69 years and most patients were
sons of patients with sepsis and septic shock during the first males (64%). When stratified for patients presenting with
week of sepsis on days 1, 3, 5, 7, and 10. Spearman’s rank sepsis or septic shock (Table 1, middle and right panel),
correlation for nonparametric data was used to test the asso- cardiovascular risk factors (including arterial hyperten-
ciation of the CRP and PCT with medical and laboratory sion, diabetes mellitus, and hyperlipidaemia) did not differ
parameters on day 1. among patients with sepsis or septic shock on admission.
Furthermore, the rates of coronary artery disease (31% vs.
36%; p = 0.305), heart failure (17% vs. 23%; p = 0.142),
Diagnostic performance of CRP and PCT and atrial fibrillation (27% vs. 29%; p = 0.673) were com-
parable in both groups. Of note, left ventricular ejection
C-statistics were applied with calculation of the receiver fraction (LVEF) < 35% was more frequently observed in
operating characteristic (ROC) and the corresponding area patients with septic shock (20% vs. 11%; p = 0.001) with
under the curve (AUC) within the entire cohort to assess increased rates of cardiopulmonary resuscitation (20% vs.
the discriminative performance of the CRP and PCT with 6%; p = 0.001).
regard to the diagnosis of septic shock and sepsis at days 1, Sepsis-related data, laboratory data, and sepsis-related
3, 5, 7, and 10. Thereafter, the diagnostic accuracy of CRP outcomes are outlined within Table 2. Established sepsis-
and PCT with regard to blood-culture confirmed sepsis was scores were higher in patients presenting with septic shock
tested. AUCs for the diagnostic performance were compared compared to patients presenting with sepsis, including the
by the method of Hanley and McNeil [16]. acute physiology score (median 18 vs. 14; p = 0.001), acute
physiology and chronic health evaluation II (APACHE
Prognostic performance of CRP and PCT II) score (median 26 vs. 22; p = 0.001) and SOFA score
(median 13 vs. 10; p = 0.001). In both groups (i.e., sepsis
C-statistics were applied with calculation of ROC and the and septic shock), a pulmonary infection was the most
corresponding AUC within the entire cohort at days 1, 3, common focus (60% vs. 59%), followed by an unknown
5, 7, and 10 with regard to the 30-day all-cause mortality. infection focus (18% vs. 21%) and urogenital infection
AUCs for prognostic performance were compared by the (14% vs. 7%). The distribution of the infectious focus did
method of Hanley and McNeil [16]. not statistically differ between both groups (p = 0.338).
Kaplan–Meier analyses according to the median CRP and Accordingly, the distribution of blood-culture positive sep-
PCT levels were performed within the entire study cohort, sis was comparable (45% vs. 49%; p = 0.386). Compared
as well as separated by clinical improvement or impairment to patients admitted with sepsis without shock, the inter-
(i.e., groups 1–4). Univariable hazard ratios (HR) were given national normalized ratio (INR) (1.3 vs. 1.2; p = 0.001)
together with 95% confidence intervals. and the aspartate aminotransferase (AST) levels (82 U/l
Results of all statistical tests were considered significant vs. 43 U/l; p = 0.001) were significantly higher in patients
for p ≤ 0.05. SPSS (Version 25, IBM, Armonk, New York) presenting with a septic shock on admission.

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460 Irish Journal of Medical Science (1971 -) (2024) 193:457–468

Table 1  Baseline characteristics

All patients (n = 349) Sepsis (n = 197) Septic shock (n = 152) p-value

Age, median; (IQR) 69 (60–79) 69 (60–79) 70 (58–80) 0.622

Male sex, n (%) 222 (63.6) 128 (65.0) 94 (61.8) 0.546
Body mass index (kg/m2), median; (IQR) 26.23 (23.44–29.41) 26.3 (22.93–29.39) 26.23 (23.67–30.04) 0.994
Entry criteria, median; (IQR)
Body temperature (°C) 36.7 (36–37.5) 36.9 (36–37.6) 36.4 (35.7–37.3) 0.014
Heart rate (bpm) 99 (86–115) 97 (85–112) 101 (87–119) 0.088
Systolic blood pressure (mmHg) 109 (94–130) 112 (99–133) 103 (88–125) 0.001
Respiratory rate (breaths/minute) 21 (18–26) 22 (18–26) 20 (17–27) 0.690
Cardiovascular risk factors, n (%)
Arterial hypertension 225 (64.5) 128 (65.0) 97 (63.8) 0.823
Diabetes mellitus 119 (34.1) 64 (32.5) 55 (36.2) 0.470
Hyperlipidemia 99 (28.4) 50 (25.4) 49 (32.2) 0.159
Smoking 99 (28.4) 55 (27.9) 44 (28.9) 0.833
Prior medical history, n (%)
Coronary artery disease 116 (33.2) 61 (31.0) 55 (36.2) 0.305
Congestive heart failure 68 (19.5) 33 (16.8) 35 (23.0) 0.142
Atrial fibrillation 97 (27.8) 53 (26.9) 44 (28.9) 0.673
Chronic kidney disease 69 (19.8) 43 (21.8) 26 (17.1) 0.272
COPD 64 (18.3) 39 (19.8) 25 (16.4) 0.423
Liver cirrhosis 33 (9.5) 15 (7.6) 18 (11.8) 0.181
Malignancy 113 (32.4) 54 (27.4) 59 (38.8) 0.024
Immunosuppression 47 (13.5) 29 (14.7) 18 (11.8) 0.435
LVEF at admission, n (%)
≥ 55% 134 (41.6) 81 (44.0) 53 (38.4) 0.001
54–45 89 (27.6) 62 (33.7) 27 (19.6)
44–35% 51 (15.8) 20 (10.9) 31 (22.5)
< 35% 48 (14.9) 21 (11.4) 27 (19.6)
Not documented 27 - 13 - 14 -
Cardiopulmonary resuscitation, n (%) 41 (11.7) 11 (5.6) 30 (19.7) 0.001
In-hospital 12 (3.4) 3 (1.5) 9 (5.9) 0.001
Out-of-hospital 29 (8.3) 8 (4.1) 21 (13.8)

COPD chronic obstructive pulmonary disease, IQR interquartile range, LVEF left ventricular ejection fraction
Level of significance p < 0.05. Bold type indicates statistical significance

Association of CRP and PCT with clinical (r =  −0.170; p = 0.005), and days of mechanical ventila-
and laboratory data tion (r =  −0.129; p = 0.034). In contrast, no correlation of
the PCT with sepsis-related scores (i.e., APACHE II, acute
Table 3 illustrates the correlation of the CRP and PCT on physiology score, and SOFA score) was found (p > 0.005).
day 1 with clinical and laboratory data. CRP significantly
correlated with creatinine (r = 0.148; p = 0.006) and pro- Diagnostic performance of CRP and PCT
calcitonin (r = 0.331; p = 0.001). However, CRP did not
correlate with other laboratory data, and no correlation The distribution of the CRP and PCT levels patients admit-
of the CRP with sepsis-related scores was found. The ted with sepsis or septic shock at days 1, 3, 5, 7, and 10 is
PCT correlated with bilirubin (r = 0.198; p = 0.002) and presented in Fig. 1. In patients admitted with sepsis, the
creatinine (r = 0.255; p = 0.001). In line, PCT correlated highest CRP level was seen on day 2 (median 167 (IQR
with platelet count (r =  −0.172; p = 0.004) and activated 109–256) mg/l). Thereafter, a continuous decline of the CRP
partial thromboplastin time (aPTT) (r = 0.244; p = 0.001), was observed until day 10. Initial CRP levels did not differ
as well as clinical parameters such as the PaO2/FiO2 ratio among patients with sepsis or septic shock (median CRP
(r = 0.125; p = 0.048), mean arterial pressure (MAP) level day 1 in sepsis: 150 (97–225) mg/l; septic shock: 127

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Irish Journal of Medical Science (1971 -) (2024) 193:457–468 461

Table 2  Sepsis-related data, follow-up data, and endpoints

All patients Sepsis Septic shock p-value
(n = 349) (n = 197) (n = 152)

Sepsis scores, median; (IQR)

DIC 1 (0–2) 1 (0–2) 2 (1–3) 0.001
Acute physiology score 16 (12–21) 14 (9–19) 18 (14–23) 0.001
APACHE II 23 (18–29) 22 (15–27) 26 (21–31) 0.001
SOFA 11 (8–13) 10 (7–12) 13 (10–15) 0.001
ISARIC-4C-Mortality score 14 (12–16) 14 (12–16) 14 (12–16) 0.709
Infection focus, n (%)
Pulmonary 207 (59.3) 118 (59.9) 89 (58.6) 0.338
Urogenital 38 (10.9) 27 (13.7) 11 (7.2)
Intra-abdominal 32 (9.2) 15 (7.6) 17 (11.2)
Wound 2 (0.6) 1 (0.5) 1 (0.7)
Unknown 67 (19.2) 35 (17.8) 32 (21.1)
SARS-CoV-2 infection, n (%) 40 (11.5) 31 (15.7) 9 (5.9) 0.004
Microbiology
Positive blood cultures, n (%) 163 (46.7) 88 (44.7) 75 (49.3) 0.386
Number of positive blood cultures per patient, median; (IQR) 0.0 (0.0–2.0) 0.0 (0.0–2.0) 0.5 (0.0–2.0) 0.616
Gram-positive bacteria, n (%)
Coagulase-negative Staphylococcus 65 (18.6) 37 (18.8) 28 (18.4) 0.932
Staphylococcus aureus 28 (8.0) 16 (8.1) 12 (7.9) 0.938
Enterococcus 24 (6.9) 14 (7.1) 10 (6.6) 0.847
Other 13 (3.7) 7 (3.6) 6 (3.9) 0.847
Gram-negative bacteria, n (%)
Escherichia coli 28 (8.0) 13 (6.6) 15 (9.9) 0.265
Klebsiella pneumoniae 15 (4.3) 8 (4.1) 7 (4.6) 0.804
Pseudomonas aeruginosa 6 (1.7) 4 (2.0) 2 (1.3) 0.611
Other 13 (3.7) 8 (4.1) 5 (3.3) 0.706
Antibiotic treatment at index, n (%)
Beta-lactam 290 (83.1) 165 (83.8) 125 (82.2) 0.707
Glycopeptide 17 (4.9) 10 (5.1) 7 (4.6) 0.839
Macrolide 18 (5.2) 11 (5.6) 7 (4.6) 0.682
Other 24 (6.9) 11 (5.6) 13 (8.6) 0.277
Multiple organ support during ICU
Vasopressor support, n (%) 308 (88.3) 157 (79.7) 151 (99.3) 0.001
Dialysis during hospitalization, n (%) 152 (43.6) 66 (33.5) 86 (56.6) 0.001
Extracorporal membrane oxygenation, n (%) 24 (6.9) 14 (7.1) 10 (6.6) 0.847
Respiratory status
Mechanical ventilation, n (%) 186 (53.3) 97 (49.2) 89 (58.6) 0.084
Invasive mechanical ventilation, n (%) 145 (41.5) 63 (32.0) 82 (53.9) 0.001
Duration of mechanical ventilation (days; mean, (range)) 5 (1–16) 7 (1–17) 4 (1–14) 0.098
­PaO2/FiO2 ratio (median; (IQR)) 197 (135–292) 198 (138–297) 196 (132–291) 0.804
­PaO2 (median; (IQR)) 89 (74–120) 86 (71–116) 92 (78–126) 0.038
Liver function
Acute liver failure, n (%) 30 (8.6) 10 (5.1) 20 (13.2) 0.008
Renal function, median; (IQR)
Creatinine (mg/dl) 1.8 (1.1–3) 1.6 (1–2.9) 1.9 (1.4–3.1) 0.555
GFR (ml/min) 32.8 (19.1–57.9) 41.1 (19.9–65.3) 30.2 (18.5–46.9) 0.002
Urine output (ml) 800 (235–1575) 980 (413–1735) 530 (100–1313) 0.022
Dialysis (days) 0 (0–4) 0 (0–4) 2 (0–5) 0.254

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462 Irish Journal of Medical Science (1971 -) (2024) 193:457–468

Table 2  (continued)
All patients Sepsis Septic shock p-value
(n = 349) (n = 197) (n = 152)

Baseline laboratory values, median; (IQR)

pH 7.37 (7.28–7.42) 7.39 (7.31–7.44) 7.33 (7.22–7.4) 0.389
Lactate (mmol/l) 2 (1.2–4.1) 1.3 (1–2) 3.6 (2.2–7.6) 0.001
Sodium (mmol/l) 139 (135–144) 139 (135–144) 139 (135–144) 0.396
Potassium (mmol/l) 4.2 (3.8–4.7) 4.2 (3.7–4.6) 4.2 (3.9–4.8) 0.038
Hemoglobin (g/dl) 9.9 (8.3–12.1) 9.9 (8.5–12.4) 10 (8.1–11.9) 0.473
WBC (­ 106/ml) 12.6 (8.1–18) 12.4 (8.3–17.1) 12.8 (7.7–19.7) 0.480
Platelets ­(106/ml) 176 (106–268) 185 (124–265) 156 (85–269) 0.275
INR 1.2 (1.1–1.4) 1.2 (1.1–1.3) 1.3 (1.1–1.6) 0.001
Fibrinogen (g/l) 3.5 (2.5–5.6) 4.5 (2.9–6.3) 3.2 (2.1–4.7) 0.016
D-dimer (µg/l) 4.4 (1.6–16.1) 3.8 (1.4–10.4) 11.6 (4.2–32) 0.001
AST (U/l) 56 (29–127) 43 (25–79) 82 (43–187) 0.011
ALT (U/l) 31 (18–72) 27 (16–56) 38 (20–92) 0.061
Bilirubin (mg/dl) 0.9 (0.5–1.7) 0.8 (0.4–1.4) 1 (0.6–2) 0.111
Troponin I (µg/l) 0.2 (0–1) 0.1 (0–0.6) 0.5 (0.1–1.7) 0.304
NT-pro BNP (pg/ml) 2786 (897–7945) 2268 (775–6895) 4860 (1008–12,742) 0.149
Procalcitonin (ng/ml) 2.8 (0.7–18.4) 1.7 (0.6–11.8) 5.2 (1–31.2) 0.248
CRP (mg/l) 144 (83–220) 150 (97–225) 127 (79–219) 0.092
Primary endpoint
All-cause mortality at 30 days, n (%) 180 (51.6) 81 (41.1) 99 (65.1) 0.001
Primary sepsis-related death at 30 days, n (%) 138 (76.7) 64 (79.0) 74 (74.7) 0.501
Primary non-sepsis-related death at 30 days, n (%) 42 (23.3) 17 (21.0) 25 (25.3)
Follow-up data, n (%)
ICU time (days; median; (IQR)) 8 (3–20) 10 (4–21) 6 (3–17) 0.042
Death ICU, n (%) 168 (48.1) 70 (35.5) 98 (64.5) 0.001

ALT alanine aminotransferase, APACHE II Acute Physiology and Chronic Health Disease Classification System II, AST aspartate aminotrans-
ferase, CRP C-reactive protein, DIC disseminated intravascular coagulation, GFR glomerular filtration rate, ICU intensive care unit, INR inter-
national normalized ratio, IQR interquartile range, NT-pro BNP N-terminal pro-B-type natriuretic peptide, SARS-CoV-2 severe acute respiratory
syndrome coronavirus type 2, SOFA sepsis-related organ failure assessment score, WBC white blood cells
Level of significance p < 0.05. Bold type indicates statistical significance

(79–219) mg/l; p = 0.092). However, in the presence of sep- Prognostic performance of CRP and PCT
tic shock, CRP was shown to increase until day 10 of ICU
hospitalization (median 179 (66–225) mg/l). In contrast, Overall risk of 30-day all-cause mortality was 52%. As
both in patients with sepsis and septic shock, the highest illustrated in Fig. 2, the PCT levels did not significantly
PCT levels were observed on day 3 (median PCT level day differ among 30-day survivors and non-survivors during
3 in sepsis: 6.81 (0.95–28.68) ng/ml; septic shock: 10.83 the first 10 days of ICU hospitalization (median PCT day
(3–18.39 ng/ml; p = 0.820)). 1 in survivors: 3.08 (0.78–30.1) ng/ml; non-survivors: 2.28
C-statistics revealed comparable but poor diagnostic (0.62–11.3) ng/ml; p = 0.083). Likewise, except for day 10
performance for PCT on day 1 (AUC = 0.590) and poor (median CRP day 10 in survivors: 90 (43–149) mg/l; non-
AUC for CRP (AUC = 0.440) to discriminate patients with survivors: 118 (67–193); p = 0.041), the CRP levels also
septic shock from those with sepsis (p for AUC differ- did not significantly differ among both groups during the
ence = 0.001). The AUCs for PCT were improved on day first 10 days of ICU hospitalization (median CRP day 1 in
7 and 10 (0.833–0.861) and moderate for CRP on day 5 to survivors: 150 (78–227) mg/l; non-survivors: 137 (88–216)
day 10 (AUC range 0.609–0.652) (Table 4). Furthermore, mg/l; p = 0.269).
the diagnostic value of CRP (AUC 0.469–0.558) and PCT The prognostic AUCs of CRP (range of AUC 0.475 to
(AUC 0.535–0.654) with regard to blood-culture positive 0.596) and PCT (range of AUC 0.456 to 0.550) were poor
sepsis was poor during the first week of ICU hospitaliza- at all time points to predict all-cause mortality at 30 days
tion (Table 5). (Table 6).

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Irish Journal of Medical Science (1971 -) (2024) 193:457–468 463

Table 3  Univariate correlations of CRP and PCT with laboratory and CRP (log rank p = 0.155; HR = 0.999; 95% CI 0.998–1.001;
clinical parameters in all patients (n = 349) at day 1 p = 0.203) (Fig. 3, left panel). Accordingly, 30-day all-cause
CRP PCT mortality was not affected by initial PCT level (52% vs.
54%; log rank p = 0.961; HR = 0.998; 95% CI 0.993–1.003;
r p-value r p-value
p = 0.500) (Fig. 3, right panel).
Age 0.016 0.766 0.050 0.409
BMI 0.031 0.575 −0.046 0.461 Prognostic impact of CRP and PCT during course
Creatinine (mg/dl) 0.148 0.006 0.255 0.001 of sepsis and septic shock
Bilirubin (mg/dl) 0.049 0.401 0.198 0.002
Albumin (g/l) −0.163 0.004 −0.123 0.058 When stratified for the dynamic change of the clinical
CRP (mg/l) - - 0.331 0.001 improvement/impairment, CRP was shown to decrease in
Procalcitonin (ng/ml) 0.331 0.001 - - patients with sepsis without shock (group 1) (mean CRP day
Hb (g/dl) −0.066 0.216 −0.013 0.834 1 164 ± 96 mg/l; mean CRP day 10 114 ± 82 mg/l; p = 0.001),
WBC ­(106/ml) 0.016 0.770 0.100 0.101 patients with initial sepsis with progression to septic shock
Platelet count ­(106/ml) −0.025 0.644 −0.172 0.004 (group 2) (mean CRP day 1 166 ± 112 mg/l; mean CRP day 10
aPPT 0.088 0.128 0.244 0.001 145 ± 81 mg/l; p = 0.437) and to decrease in patients with sep-
PaO2/FiO2 ratio 0.015 0.785 0.125 0.048 tic shock improving to sepsis without shock (group 3) (mean
MAP (mmHg) −0.002 0.969 −0.170 0.005 CRP day 1 153 ± 108 mg/l; mean CRP day 10 102 ± 70 mg/l;
Intensive care days 0.029 0.591 −0.118 0.052 p = 0.001), as well as in patients with septic shock without clin-
Mechanical ventilation days 0.009 0.870 −0.129 0.034 ical improvement (group 4) (mean CRP day 1 136 ± 85 mg/l;
Renal replacement days 0.070 0.192 0.033 0.591 mean CRP day 10 121 ± 60 mg/l; p = 0.797) (Fig. 4). In line,
Catecholamine use −0.029 0.591 −0.013 0.831 PCT levels were shown to decrease during the first 10 days of
SOFA score 0.002 0.970 0.105 0.083 ICU hospitalization within the analyzed subgroups.
Acute physiology score −0.093 0.084 0.074 0.223 When stratified for clinical improvement or impairment
APACHE II score −0.086 0.110 0.100 0.100 according to the above-mentioned subgroups, both CRP and
PCT were not shown to be associated with 30-day all-cause
APACHE II acute physiology and chronic health evaluation II, BMI
body mass index, CRP C-reactive protein, INR international normal- mortality within pre-specified subgroups (i.e., initial sep-
ized ratio, aPPT activated partial thromboplastin time, SOFA sepsis- sis without impairment; initial sepsis progressing to sep-
related organ failure assessment score, Hb haemoglobin, WBC white tic shock; initial septic shock improving to sepsis without
blood cells
shock; and initial septic shock without clinical improvement)
Level of significance p < 0.05. Bold type indicates statistical signifi-
(Figs. 5 and 6).
cance

Diagnostic and prognostic value of CRP and PCT

When stratified for the median CRP and PCT levels on day after exclusion of patients with COVID‑19 disease
1, all-cause mortality occurred in 55% of the patients with
CRP ≤ 144 mg/l and 48% with CRP > 144 mg/l at 30 days. Even after exclusion of patients with sepsis related to
Accordingly, risk of all-cause mortality was not affected by COVID-19 disease, the diagnostic value of CRP on day 1 to
discriminate patients with septic shock (AUC = 0.436; 95%
S e p s is S e p tic s h o c k
CI 0.371–0.500; p = 0.052) was poor. Accordingly, the diag-
300
M e d ia n
300
M e d ia n nostic value of PCT was poor to moderate (AUC = 0.578;
95% CI 0.505–0.651; p = 0.036). Furthermore, both the
7 5 % P e r c e n tile 7 5 % P e r c e n tile
200 2 5 % P e r c e n tile 200 2 5 % P e r c e n tile
C R P (m g /l)

C R P (m g /l)

prognostic value with regard to 30-day all-cause mortality

n d1 = 1 9 7 n d1 = 1 5 2
n d2 = 2 2 0 n d2 = 9 1
n d3 = 2 1 0 n d3 = 6 1
100 100

of CRP (AUC = 0.467; 95% CI 0.311—0.402; p = 0.311) and

n d5 = 1 8 6 n d5 = 2 2
n d7 = 1 5 6 n d7 = 1 9
n d10 = 1 3 6 n d10 = 1 0

PCT (AUC = 0.455; 95% CI 0.382–0.528; p = 0.221) was

0 0
1 2 3 5 7 10 1 2 3 5 7 10

T im e in d a y s T im e in d a y s

40
S e p s is

40
S e p tic s h o c k
poor and comparable to the AUCs including COVID-19
patients (p > 0.05) (data not shown).
M e d ia n M e d ia n

7 5 % P e r c e n tile 7 5 % P e r c e n tile
30 30
2 5 % P e r c e n tile 2 5 % P e r c e n tile
P C T ( n g /m l)

P C T ( n g /m l)

20 n d1 = 1 5 1 20 n d1 = 1 2 0
n d2 = 1 0 5 n d2 = 5 5
n d3 = 8 6 n d3 = 3 4
n d5 = 5 7 n d5 = 1 0
10 10
n d7 = 3 6 n d7 = 8

Discussion
n d10 = 3 0 n d10 = 4

0 0
1 2 3 5 7 10 1 2 3 5 7 10

T im e in d a y s T im e in d a y s

The present study comprehensively investigates the diag-

Fig. 1  Distribution of CRP and PCT among patients with sepsis and
septic shock during the first 10 days of sepsis onset (i.e., on days 1, 3, nostic and prognostic role of CRP and PCT in patients
5, 7, and 10). Data is presented as median with interquartile ranges admitted with sepsis or septic shock. This data suggests

13
464 Irish Journal of Medical Science (1971 -) (2024) 193:457–468

Table 4  C-statistic for CRP PCT p-value

biomarkers to discriminate for AUC
between sepsis and septic shock difference
at days 1, 3, 5, 7, and 10
Day 1 0.440 (0.379–0.501); p = 0.054 0.590 (0.520–0.659); p = 0.011 0.001
Day 1: Controls n = 197 patients with sepsis
Day 3 0.507 (0.427–0.586); p = 0.875 0.568 (0.461–0.675); p = 0.248 0.401
Day 3: Controls n = 212 patients with sepsis
Day 5 0.609 (0.486–0.733); p = 0.094 0.452 (0.278–0.616); p = 0.628 0.182
Day 5: Controls n = 188 patients with sepsis
Day 7 0.628 (0.502–0753); p = 0.070 0.861 (0.695–1.000); p = 0.002 0.038
Day 7: Controls n = 158 patients with sepsis
Day 10 0.652 (0.443–0.862); p = 0.109 0.833 (0.697–0.969); p = 0.033 0.265
Day 10: Controls n = 138 patients with sepsis

Level of significance p < 0.05. Bold type indicates statistical significance

Table 5  C-statistic for CRP PCT p-value

biomarkers to discriminate for AUC
between positive and negative difference
blood cultures at days 1, 3, 5,
7, and 10 Day 1 0.507 (0.446–0.568); p = 0.814 0.578 (0.510–0.647); p = 0.026 0.127
Day 3 0.558 (0.490–0.626); p = 0.098 0.616 (0.516–0.717); p = 0.028 0.349
Day 5 0.515 (0.436–0.593); p = 0.714 0.654 (0.520–0.787); p = 0.033 0.073
Day 7 0.510 (0.424–0.597); p = 0.812 0.535 (0.363–0.707); p = 0.700 0.802
Day 10 0.469 (0.374–0.563); p = 0.512 0.588 (0.385–0.791); p = 0.386 0.283

Level of significance p < 0.05. Bold type indicates statistical significance

CRP has a poor diagnostic accuracy to discriminate stratified for clinical improvement or impairment during
between patients with sepsis and septic shock compared course of ICU hospitalization, CRP and PCT were not
to PCT. PCT was shown to have a good diagnostic accu- associated with the risk of 30-day all-cause mortality.
racy on day 7 and 10 (AUC 0.833–0.861). In contrast, CRP The diagnostic value of CRP and PCT was investigated
and PCT were shown to have a poor prognostic value with within various registries with conflicting findings. Silvestre
regard to 30-day all-cause mortality. Both CRP and PCT et al. investigated the diagnostic and prognostic role of CRP
levels did not affect the risk of 30-day all-cause mortal- in 158 patients with sepsis, severe sepsis, and septic shock
ity in patients with sepsis and septic shock. Even when using a prospective registry. They found no association of the
CRP concentration on day 1 with the severity of the sepsis.
S u r v iv o r N o n - s u r v iv o r
Furthermore, higher CRP concentrations were not associated
300
M e d ia n
300
M e d ia n with an increased risk of ICU mortality [13]. In line, the
diagnostic and prognostic values of CRP, PCT, and presepsin
7 5 % P e r c e n tile 7 5 % P e r c e n tile
200 2 5 % P e r c e n tile 200 2 5 % P e r c e n tile
C R P (m g /l)

C R P (m g /l)

were investigated by Lee et al. including 420 patients with

n d1 = 1 6 9 n d1 = 1 8 0
n d2 = 1 6 1 n d2 = 1 5 0
n d3 = 1 4 5 n d3 = 1 3 0
100 100

non-infectious organ failure, sepsis, and septic shock. Prese-

n d5 = 1 2 0 n d5 = 9 0
n d7 = 1 0 5 n d7 = 7 0
n d10 = 9 1 n d10 = 5 5

psin and PCT were able to discriminate the diagnosis septic

0 0
1 2 3 5 7 10 1 2 3 5 7 10

T im e in d a y s T im e in d a y s

40
S u r v iv o r

40
N o n - s u r v iv o r
shock from sepsis, whereas CRP was not shown to discrimi-
nate septic shock from sepsis. Furthermore, presepsin was
M e d ia n M e d ia n

7 5 % P e r c e n tile 7 5 % P e r c e n tile
30 30
2 5 % P e r c e n tile 2 5 % P e r c e n tile

shown to be predictive for 28-day all-cause mortality, which

P C T ( n g /m l)

P C T ( n g /m l)

20 n d1 = 1 2 7 20 n d1 = 1 4 4
n d2 = 8 1 n d2 = 7 9

was still proven after multivariable Cox regression analyses.

n d3 = 6 0 n d3 = 6 1
n d5 = 3 0 n d5 = 3 7
10 10
n d7 = 2 1 n d7 = 2 3

In contrast, CRP and PCT levels did not differ among 28-day
n d10 = 1 9 n d10 = 1 5

0 0
1 2 3 5 7 10 1 2 3 5 7 10

survivors and non-survivors; however, their analyses were

T im e in d a y s T im e in d a y s

based on a single biomarker assessment [5]. The present study

Fig. 2  Distribution of CRP and PCT among 30-day survivors and
non-survivors on days 1, 3, 5, 7, and 10. Data is presented as median confirms no prognostic impact of CRP and PCT levels in
with interquartile ranges patients with sepsis and septic shock - which is line with

13
Irish Journal of Medical Science (1971 -) (2024) 193:457–468 465

Table 6  C-statistic for CRP PCT p-value

biomarkers at days 1, 3, 5, 7, for AUC
and 10 to discriminate between difference
non-survivors and survivors of
the 30-day time interval Day 1 0.475 (0.414–0.536); p = 0.416 0.456 (0.386–0.525); p = 0.208 0.685
Day 1: Controls n = 197 patients with sepsis
Day 3 0.507 (0.439–0.575); p = 0.840 0.512 (0.407–0.617); p = 0.820 0.937
Day 3: Controls n = 212 patients with sepsis
Day 5 0.558 (0.479–0.636); p = 0.153 0.550 (0.401–0.698); p = 0.488 0.922
Day 5: Controls n = 188 patients with sepsis
Day 7 0.568 (0.481–0.655); p = 0.129 0.531 (0.352–0.710); p = 0.724 0.707
Day 7: Controls n = 158 patients with sepsis
Day 10 0.596 (0.501–0.692); p = 0.052 0.521 (0.313–0.730); p = 0.835 0.505
Day 10: Controls n = 138 patients with sepsis

Level of significance p < 0.05. Bold type indicates statistical significance

reports from our study group from the year 2004 [3]. But still in have good diagnostic accuracy from day 7 to day 10 (AUC
the sepsis-3 era modern intensive care for patients with septic 0.833–0.861), whereas the diagnostic value during the
shock, these commonly applied inflammatory markers do not early stages of sepsis and septic shock was poor. In line, the
reveal a relevant diagnostic and prognostic impact in this setting.
Of note, a microbacterial-proven sepsis is only reported Group 1 Group 2

in 30–40% of patients admitted with sepsis or septic shock Log rank p = 0.635 Log rank p = 0.454

[6]. Both CPR and PCT were not shown to be predictive for
Survival

Survival
microbacterial-proven sepsis in 157 patients with suspected CRP ≤ 151 mg/l CRP > 151 mg/l
All-cause
CRP ≤ 147 mg/l CRP > 147 mg/l

sepsis (AUC 0.53 and 0.55). Furthermore, the decline of

All-cause (n=81; 52%) (n=76; 48%) (n=20; 51%) (n=19; 49%)
mortality, n(%) mortality, n(%)
31 (38) 26 (34) 14 (70) 10 (53)

Days of survival Days of survival

5 days to baseline CRP and PCT did not significantly differ

Pa ents at risk Pa ents at risk
CRP ≤ 151 mg/l 81 69 54 50 CRP ≤ 147 mg/l 20 15 9 6
CRP > 151 mg/l 76 61 56 50 CRP > 147 mg/l 19 12 11 9

among 28-day non-survivors compared to survivors [17]. Group 3 Group 4

The present study specifically focused on the diagnostic Log rank p = 0.601 Log rank p = 0.214

CRP ≤ 117 mg/l CRP > 117 mg/l

and prognostic impact of CRP and PCT during the course

All-cause (n=27; 51%) (n=26; 49%)

Survival
Survival

mortality, n(%)
27 (100) 24 (92)

of ICU treatment. Of note, specifically PCT was shown to All-cause

CRP ≤ 129 mg/l CRP > 129 mg/l
(n=50; 51%) (n=49; 49%)
mortality, n(%)
23 (46) 25 (51)

Days of survival Days of survival

Pa ents at risk Pa ents at risk
CRP ≤ 129 mg/l 50 37 34 27 CRP ≤ 117 mg/l 27 1 0 0
CRP > 129 mg/l 49 34 30 24 CRP > 117 mg/l 26 3 2 2

Log rank p = 0.155 Log rank p = 0.961

Fig. 5  Kaplan–Meier curves for CRP with regard to all-cause mortal-

Survival

Survival

PCT ≤ 2.75 ng/ml PCT > 2.75 ng/ml

ity at 30 days stratified by dynamic disease progression/improvement
during ICU hospitalization
CRP ≤ 144 mg/l CRP > 144 mg/l
All-cause All-cause (n=136; 50%) (n=134; 50%)
(n=175; 50%) (n=174; 50%)
mortality, n(%) mortality, n(%)
97 (55) 83 (48) 74 (54) 70 (52)

Days of survival Days of survival

Pa ents at risk Pa ents at risk
CRP ≤ 144 mg/l 175 115 92 78 PCT ≤ 2.75 ng/ml 136 94 76 62
CRP > 144 mg/l 174 118 15 91 PCT > 2.75 ng/ml 134 84 71 64

Group 1 Group 2

Fig. 3  Kaplan–Meier curves for CRP and PCT with regard to all- Log rank p = 0.187 Log rank p = 0.074

cause mortality at 30 days within the entire study cohort

Survival

Survival

PCT ≤ 1.47 ng/ml PCT > 1.47 ng/ml PCT ≤ 2.32 ng/ml PCT > 2.32 ng/ml
All-cause All-cause (n=17; 50%) (n=17; 50%)
(n=58; 50%) (n=58; 50%)
mortality, n(%) mortality, n(%)
C-reac ve protein Procalcitonin 26 (45) 19 (33) 13 (76) 8 (47)

200 40
G ro u p 1 G ro u p 1 Days of survival Days of survival
Pa ents at risk Pa ents at risk
PCT ≤ 1.47 ng/ml 58 45 36 32 PCT ≤ 2.32 ng/ml 17 11 7 4
G ro u p 2 G ro u p 2
30 PCT > 1.47 ng/ml 58 50 42 39 PCT > 2.32 ng/ml 17 13 11 9
G ro u p 3 G ro u p 3
P C T ( n g /m l)
C R P (m g /l)

150
G ro u p 4 G ro u p 4
20
G ro u p 1 G ro u p 2 G ro u p 3 G ro u p 4 G ro u p 1 G ro u p 2 G ro u p 3 G ro u p 4
n d1 = 1 4 5 n d1 = 3 9 n d1 = 9 9 n d1 = 5 3 n d1 = 1 1 6 n d1 = 3 4 n d1 = 7 8 n d1 = 4 2
n d2 = 1 4 1 n d2 = 3 7 n d2 = 9 6 n d2 = 3 6 n d2 = 6 5 n d2 = 1 8 n d2 = 5 5 n d2 = 2 2
Group 3 Group 4
10
100 n d3 = 1 2 6 n d3 = 3 6 n d3 = 9 1 n d3 = 2 1 n d3 = 4 9 n d3 = 1 8 n d3 = 4 2 n d3 = 1 2
n d5 = 1 0 0 n d5 = 2 9 n d5 = 7 2 n d5 = 8 n d5 = 2 9 n d5 = 1 0 n d5 = 2 3 n d5 = 5 Log rank p = 0.097 Log rank p = 0.989
n d7 = 8 9 n d7 = 2 7 n d7 = 5 3 n d7 = 5 n d7 = 2 0 n d7 = 8 n d7 = 1 3 n d7 = 3
0
n d10 = 7 2 n d10 = 2 3 n d10 = 4 8 n d10 = 2 n d10 = 2 0 n d10 = 3 n d10 = 1 0 n d10 = 1
1 2 3 5 7 10 1 2 3 5 7 11
PCT ≤ 6.03 ng/ml PCT > 6.03 ng/ml
All-cause (n=21; 50%) (n=21; 50%)
Survival

Survival

T im e in d a y s T im e in d a y s mortality, n(%)
20 (95) 20 (95)

Fig. 4  Dynamic changes of CRP (left panel) and PCT (right panel)
PCT ≤ 4.24 ng/ml PCT > 4.24 ng/ml
All-cause (n=39; 50%) (n=39; 50%)
mortality, n(%)
23 (59) 15 (38)

within pre-specified subgroups: (group 1) patients with initial sepsis Pa ents at risk
PCT ≤ 4.24 ng/ml 39 26
Days of survival
23 16
Pa ents at risk
PCT ≤ 6.03 ng/ml 21 2
Days of survival
1 1

without progression to septic shock; (group 2) patients with initial

PCT > 4.24 ng/ml 39 29 26 24 PCT > 6.03 ng/ml 21 2 1 1

sepsis with progression to septic shock; (group 3) patients with ini-

tial septic shock with clinical improvement to sepsis without shock; Fig. 6  Kaplan–Meier curves for PCT with regard to all-cause mortal-
(group 4) patients with initial septic shock without clinical improve- ity at 30 days stratified by dynamic disease progression/improvement
ment to sepsis without shock during ICU hospitalization

13
466 Irish Journal of Medical Science (1971 -) (2024) 193:457–468

present study suggested poor diagnostic value of both CRP were shown to be at increased risk of death (corresponding
and PCT with regard to blood-culture positive sepsis. mortality rate 62% versus 36% in patients without clinical
Various studies investigated the prognostic role of CRP impairment). This data suggests a decline of CRP levels may
and PCT in patients with sepsis with conflicting findings. not an appropriate tool to detect clinical improvement dur-
Koozi et al. found an increased risk of mortality in patients ing course of ICU treatment. This may further emphasize
with CRP > 100 mg/l including 851 patients with sepsis the need to investigate the prognostic role of blood-derived
[18]. In line, the prognostic value of CRP was studied in biomarkers that may correlate with clinical improvement/
313 patients admitted to the ICU, which was not restricted impairment during course of sepsis or septic shock.
to patients with sepsis. Increasing CRP levels were associ- In contrast, the NLR is linked to elevated levels of
ated with more severe organ dysfunction, longer ICU stay, proinflammatory cytokines in patients with sepsis or sep-
and increased risk of all-cause mortality. Furthermore, an tic shock and was shown to predict outcomes in patients
increase of CRP after 48 h was associated with an increased with infectious disease, cancer, and in patients following
risk of all-cause mortality [19]. These findings are in line surgery. As a result of its rapid increase (commonly within
with a study by Wang et al. that included 576 ICU patients, 6 h), the NLR may be useful to predict sepsis severity [27].
of which 6% presented with sepsis. The authors demon- Li et al. recently demonstrated the prognostic accuracy for
strated a reliable prognostic value of the CRP to predict ICU short-term death in 302 septic patients was improved, when
mortality (AUC = 0.65) [20]. combining established sepsis-scores (such as the SOFA and
Although PCT is often postulated to have a higher prog- APACHE II scores) with the NLR [28]. However, on the
nostic value than CRP, PCT was not shown to be associated contrary, the NLR may be increased in various clinical con-
with 28-day all-cause mortality in 371 patients with signs ditions and further studies did not observe an interaction
of infection [21]. In line, a study by Gornet et al. found both of the NLR and risk prediction in patients with sepsis or
PCT and CRP to have moderate discrimination for bacte- septic shock [29, 30]. Related to the rather small number
raemia in 459 patients with suspected infection (AUC 0.68 of studies investigating the prognostic role of the NLR in
and 0.65), whereas the discrimination for 28-day all-cause septic patients compared to CRP and PCT, the NLR was
mortality was poor and even inferior to systolic blood pres- infrequently assessed within the present real-life registry and
sure and pulse oximetry [22]. The prognostic value of CRP, no follow-up measurements of the NLR were performed.
PCT, and the neutrophil-to-lymphocyte ratio (NLR) was Therefore, the present study underlines the need to further
comprehensively investigated within a retrospective study assess inflammatory biomarkers in patients with sepsis and
including 146 patients with bloodstream infection and sepsis septic shock.
according to the sepsis-3 criteria. Using multivariable Cox In conclusion, the present study suggests a superior pre-
regression analyses, the authors demonstrated that especially dictive value of the PCT compared to the CRP for the diag-
PCT and NLR were associated with 28-day mortality. Both nosis of a septic shock. In contrast, both CRP and PCT had
PCT and NLR revealed a reliable prognostic discrimination a poor predictive value for 30-day all-cause mortality. CRP
(AUC 0.830 and 0.791) for 28-day all-cause mortality [23]. and PCT were shown to decrease irrespective of clinical
However, no risk stratification was performed according to improvement or impairment, but did not affect 30-day all-
the severity of sepsis and no dynamic changes of CRP, PCT, cause mortality when stratified for clinical improvement or
and NLR during the course of sepsis were assessed. The impairment during course of ICU hospitalization.
findings of the present study are in line with previous studies
that found a poor discrimination for early sepsis-related mor-
tality based on a single biomarker, specifically in the absence Study limitations
of assessment of dynamic changes of biomarker levels [24].
The kinetics of CRP and PCT levels during the course This study has several limitations. Due to the single-center
of septic shock were investigated within a study by Bahloul and observational study design, results may be influenced
et al. including 60 patients, demonstrating a fall in CRP or by measured an unmeasured confounding. Although it was
PCT level was associated with improved prognosis [25]. On shown that IL-6 is associated with prognosis in critically ill
the other hand, CRP and PCT were inferior to interleukin-6 and septic patients, IL-6 is not measured in clinic routine at
(IL-6) predicting treatment success in 328 patients with sep- our institution and was therefore beyond the scope of this
sis when re-assessed after 48–72 h [26]. Within the present registry [31]. With regard to the diagnostic value of inflam-
study, a continuous decline in CRP from day 1 to day 10 matory markers, no control group with healthy individuals
was observed, which was irrespective of clinical improve- was considered. Furthermore, side effects regarding treat-
ment or impairment. CRP levels were also demonstrated to ment with antibiotics were not assessed for the present study.
decrease in patients with initial sepsis progressing to septic Finally, the effect of inflammatory markers on long-term
shock during the course of ICU treatment. These patients outcomes was beyond the scope of the present study.

13
Irish Journal of Medical Science (1971 -) (2024) 193:457–468 467

Funding Open Access funding enabled and organized by Projekt 13. Silvestre J, Póvoa P, Coelho L et al (2009) Is C-reactive protein
DEAL. a good prognostic marker in septic patients? Intensive Care Med
35(5):909–913
Data availability The datasets used and/or analyzed during the cur- 14. Cui N, Zhang H, Chen Z, Yu Z (2019) Prognostic significance of
rent study are available from the corresponding author on reasonable PCT and CRP evaluation for adult ICU patients with sepsis and
request. septic shock: retrospective analysis of 59 cases. J Int Med Res
47(4):1573–1579
Declarations 15. Forner J, Schupp T, Weidner K et al (2022) Cardiac troponin I
reveals diagnostic and prognostic superiority to aminoterminal
Conflict of interest The authors declare no competing interests. pro-B-type natriuretic peptide in sepsis and septic shock. J Clin
Med 11(21)
Open Access This article is licensed under a Creative Commons Attri- 16. Hanley JA, McNeil BJ (1983) A method of comparing the areas
bution 4.0 International License, which permits use, sharing, adapta- under receiver operating characteristic curves derived from the
tion, distribution and reproduction in any medium or format, as long same cases. Radiology 148(3):839–843
as you give appropriate credit to the original author(s) and the source, 17. van Oers JAH, de Jong E, Kemperman H et al (2020) Diagnostic
provide a link to the Creative Commons licence, and indicate if changes accuracy of procalcitonin and C-reactive protein is insufficient
were made. The images or other third party material in this article are to predict proven infection: a retrospective cohort study in criti-
included in the article's Creative Commons licence, unless indicated cally ill patients fulfilling the Sepsis-3 criteria. J Appl Lab Med
otherwise in a credit line to the material. If material is not included in 5(1):62–72
the article's Creative Commons licence and your intended use is not 18. Koozi H, Lengquist M, Frigyesi A (2020) C-reactive protein as a
permitted by statutory regulation or exceeds the permitted use, you will prognostic factor in intensive care admissions for sepsis: a Swed-
need to obtain permission directly from the copyright holder. To view a ish multicenter study. J Crit Care 56:73–79
copy of this licence, visit http://​creat​iveco​mmons.​org/​licen​ses/​by/4.​0/. 19. Lobo SMA, Lobo FRM, Bota DP et al (2003) C-reactive protein
levels correlate with mortality and organ failure in critically ill
­patientsa. Chest 123(6):2043–2049
20. Wang F, Pan W, Pan S et al (2011) Usefulness of N-terminal
pro-brain natriuretic peptide and C-reactive protein to predict
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