European Journal of Cardiovascular Medicine

Sepsis is a critical medical condition characterised by life-threatening organ dysfunction arising from a dysregulated host response to infection [1]. It remains a major contributor to hospital mortality, with an estimated 48.9 million cases and 11 million sepsis-related deaths reported globally in 2017 [2]. Despite improvements in intensive care, mortality rates in severe sepsis and septic shock remain high, ranging from 20% to over 50% in some populations [3]. Early diagnosis and prompt initiation of targeted antimicrobial therapy are essential to improving clinical outcomes [4].

Blood culture continues to be regarded as the gold standard for identifying causative pathogens, guiding antimicrobial stewardship, and confirming bloodstream infections [5]. However, its diagnostic yield can be influenced by prior antibiotic exposure, low-level bacteraemia, and technical variables such as volume and timing of sampling [6]. Moreover, culture results typically require 24–72 hours, creating a diagnostic gap during which empirical therapy must be initiated [7]. In this window, biochemical markers offer a potential solution for early risk stratification and therapeutic guidance.

Procalcitonin (PCT), the prohormone of calcitonin, is normally produced in small quantities by thyroid C cells but is released in large amounts by extrathyroidal tissues during bacterial infections, mediated by pro-inflammatory cytokines such as interleukin (IL)-1β, tumour necrosis factor (TNF)-α, and IL-6 [8, 9]. Unlike other acute-phase reactants, PCT levels rise rapidly within 4–6 hours of infection onset and decline with effective treatment [10]. Several studies have demonstrated its superior specificity compared to C-reactive protein (CRP) in distinguishing bacterial from viral or non-infectious inflammatory causes [11, 12].

CRP, a pentraxin-family acute-phase protein synthesised by the liver, remains one of the most widely used inflammatory biomarkers [13]. It rises within 6–8 hours of inflammatory stimulus and peaks within 48 hours [14]. While it is sensitive, its specificity for bacterial infection is lower, as levels can also rise in autoimmune diseases, trauma, and malignancies [15]. Nonetheless, CRP remains clinically valuable due to its low cost, wide availability, and utility in monitoring disease trends [16].

In recent years, there has been increasing recognition of the cardiovascular consequences of sepsis, particularly sepsis-induced myocardial dysfunction (SIMD) [17]. This reversible form of cardiac impairment occurs in approximately 40–50% of septic patients [18] and is characterised by biventricular dilatation, reduced ejection fraction, and impaired diastolic function. The pathophysiology involves a complex interplay of inflammatory cytokines, nitric oxide overproduction, mitochondrial dysfunction, and microvascular dysregulation [19]. Clinical studies have demonstrated that SIMD is associated with higher mortality rates, prolonged ICU stay, and increased risk of multi-organ failure [20].

While echocardiography and cardiac biomarkers such as troponins and NT-proBNP are standard tools for diagnosing cardiac involvement in sepsis [21], there is emerging evidence that systemic inflammatory markers like PCT and CRP may correlate with the severity of cardiovascular dysfunction [22]. Inflammatory mediators involved in sepsis not only drive systemic immune responses but also directly impair cardiomyocyte contractility and promote endothelial dysfunction [23]. Elevated PCT and CRP levels could thus reflect both infectious burden and the degree of cardiac injury in septic patients.

Despite these insights, there is a paucity of literature integrating microbiological confirmation, systemic inflammatory biomarkers, and cardiovascular assessment in a unified study. Most research has examined PCT and CRP independently or focused solely on their diagnostic accuracy for infection without correlating them with cardiac outcomes. Evaluating these parameters in tandem could offer a more comprehensive approach to early sepsis management — identifying patients at higher risk of both persistent bacteraemia and septic cardiomyopathy.

The present study aims to fill this gap by investigating the correlation of serum PCT and CRP levels with blood culture positivity and cardiovascular dysfunction, as assessed by echocardiography and relevant cardiac biomarkers, in adult patients with clinically suspected sepsis admitted to a tertiary care teaching hospital. This integrated approach is expected to improve diagnostic precision, enable earlier initiation of appropriate antimicrobial therapy, and facilitate timely cardiovascular support interventions.

Study Design and Setting

This was a prospective, observational study conducted jointly by the Departments of Microbiology, Biochemistry, and Cardiology at Mahatma Gandhi Memorial (MGM) Hospital, Warangal, Telangana, India, a tertiary care teaching hospital with a multidisciplinary critical care facility. The study period extended over 12 consecutive months, from January 2022 to December 2022.

Study Population

Adult patients aged 18 years and above, admitted to the hospital with clinical suspicion of sepsis as per Sepsis-3 criteria — defined as suspected or documented infection plus an acute increase in Sequential Organ Failure Assessment (SOFA) score by ≥2 points — were considered for inclusion. Patients were enrolled from medical, surgical, and intensive care units after fulfilling the eligibility criteria.

Inclusion Criteria

The study included adult patients aged 18 years and above who presented with clinically suspected sepsis. Only those from whom blood samples could be collected prior to the initiation of antimicrobial therapy were considered eligible. In addition, participation required the willingness of the patient or, in cases where the patient was unable to provide consent, a legally authorised representative to provide informed consent.

Exclusion Criteria

Patients were excluded if they had received antibiotic therapy within the 48 hours preceding enrolment, as prior antimicrobial exposure could affect both culture yield and biomarker levels. Individuals with known chronic inflammatory or autoimmune diseases, which might elevate baseline CRP or PCT levels independent of infection, were also excluded. Those with end-stage cardiac failure unrelated to sepsis were not considered eligible, in order to avoid confounding in the assessment of sepsis-associated cardiovascular dysfunction. Additionally, patients who were unwilling to participate or whose clinical or laboratory data were incomplete were excluded from the study.

Sample Size Calculation

The required sample size was estimated using the formula for diagnostic accuracy studies, considering an expected sensitivity of procalcitonin for predicting culture-positive sepsis of 85%, a confidence level of 95%, and a margin of error of 5% [1]. This yielded a minimum sample size of 196 patients. To account for possible attrition or incomplete records, a total of 210 patients were enrolled.

Ethical Considerations

The study protocol was reviewed and approved by the Institutional Ethics Committee of Kakatiya Medical College/MGM Hospital, Warangal (IEC approval no. KIEC/2022/MD/202205). Written informed consent was obtained from each participant or their legally authorised representative before inclusion. All procedures adhered to the ethical principles outlined in the Declaration of Helsinki (2013 revision).

Data and Sample Collection

Following initial clinical evaluation, demographic details, presenting symptoms, vital signs, comorbidities, and SOFA scores were recorded. Venous blood samples were collected under aseptic precautions prior to antibiotic administration. Two sets of blood cultures were drawn from separate venipuncture sites into aerobic and anaerobic culture bottles (BD BACTEC™ system). Concurrently, additional blood samples were collected for serum PCT, CRP, complete blood count, renal and liver function tests, and cardiac biomarkers.

Microbiological Analysis

Blood culture bottles were incubated in the automated BACTEC™ system and monitored for up to five days. Positive cultures were subcultured onto appropriate media, and isolates were identified using standard biochemical tests and, where necessary, automated identification systems (VITEK® 2, bioMérieux). Antimicrobial susceptibility testing was performed using the Kirby-Bauer disk diffusion method in accordance with CLSI guidelines (2022 update). Contaminated cultures were excluded from final analysis.

Biochemical Assays

Serum procalcitonin levels were quantified using a fully automated chemiluminescent immunoassay analyser (BRAHMS PCT, Thermo Fisher Scientific). C-reactive protein levels were measured using an immunoturbidimetric assay on an automated biochemistry platform (Beckman Coulter AU series). Both assays were performed according to the manufacturer’s protocols, and internal quality control procedures were strictly followed.

Cardiovascular Assessment

Within the first 24 hours of admission, all enrolled patients underwent transthoracic echocardiography performed by an experienced cardiologist who was blinded to microbiological results. Parameters assessed included left ventricular ejection fraction (LVEF), fractional shortening, diastolic function, and right ventricular performance. Cardiovascular dysfunction was defined as LVEF <50% and/or elevated NT-proBNP (>300 pg/mL) in the absence of pre-existing structural heart disease. Electrocardiographic findings and hemodynamic monitoring were also documented.

Statistical Analysis

Data were analysed using Statistical Package for the Social Sciences (SPSS) version 26.0 (IBM Corp., Armonk, NY, USA). Continuous variables were tested for normality using the Kolmogorov–Smirnov test and expressed as mean ± standard deviation (SD) or median with interquartile range (IQR) as appropriate. Categorical variables were presented as frequencies and percentages. The Mann–Whitney U test or Student’s t-test was used to compare continuous variables between groups, and the chi-square or Fisher’s exact test was used for categorical variables. Diagnostic performance of PCT and CRP for predicting blood culture positivity and cardiovascular dysfunction was assessed using receiver operating characteristic (ROC) curve analysis, with calculation of the area under the curve (AUC), sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). A p-value <0.05 was considered statistically significant.

A total of 210 adult patients meeting the inclusion criteria were enrolled in the study. The mean age of the participants was 54.2 years (± 15.8), with ages ranging from 18 to 89 years. The age distribution indicated that middle-aged and elderly individuals formed the largest proportion of the cohort, reflecting the higher susceptibility of these age groups to sepsis. There was a male predominance, with 124 patients (59.0%) being male, giving a male-to-female ratio of approximately 1.4:1.

Regarding comorbid conditions, diabetes mellitus was the most prevalent, affecting 72 patients (34.3%). This aligns with established evidence that diabetes predisposes individuals to infections and sepsis due to impaired immune function and microvascular changes. Hypertension was the second most common comorbidity, present in 65 patients (31.0%), while chronic kidney disease (CKD) was documented in 28 patients (13.3%). The presence of CKD is clinically significant as it often necessitates cautious fluid and drug management in septic patients and is associated with poorer outcomes.

The severity of illness at presentation was assessed using the SOFA score. The median SOFA score was 6, with an interquartile range (IQR) of 4 to 8, suggesting that most patients presented with moderate to severe organ dysfunction at admission. This score distribution underscores the critical nature of illness in this cohort and reflects the high-acuity patient population typically managed in a tertiary care hospital setting (Table 1).

Overall, the demographic profile, comorbidity burden, and SOFA score distribution highlight that the study population represented a high-risk group for adverse outcomes, making them particularly relevant for evaluating biomarkers such as procalcitonin and CRP in the context of sepsis diagnosis and prognosis.

Table 1: Demographic and clinical baseline characteristics of the study population

Out of 92 culture-positive cases, Gram-negative bacilli accounted for the majority of isolates (n = 52, 56.5%). Among them, Klebsiella pneumoniae (n = 21, 22.8%) emerged as the single most frequently isolated pathogen, followed closely by Escherichia coli (n = 19, 20.7%). Other Gram-negative isolates included Pseudomonas aeruginosa and Acinetobacter baumannii, though at much lower frequencies. The predominance of these organisms is consistent with the known epidemiology of hospital-acquired and community-acquired sepsis in developing countries, where extended-spectrum β-lactamase (ESBL) production and multidrug resistance are prevalent concerns.

Gram-positive cocci accounted for 38.0% of isolates (n = 35). Staphylococcus aureus was the leading Gram-positive organism (n = 18, 19.6%), followed by Enterococcus faecalis (n = 10, 10.9%). Both methicillin-resistant S. aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) phenotypes were identified, underscoring the challenge of managing Gram-positive sepsis in tertiary care settings.

Fungal pathogens were detected in 5.4% of cases (n = 5), all of which belonged to Candida species, including Candida albicans and Candida tropicalis. The isolation of these opportunistic fungi, although less frequent, is clinically significant as it often reflects underlying immunosuppression, prolonged ICU stays, or prior broad-spectrum antibiotic exposure (Table 2).

This distribution pattern indicates a clear predominance of Gram-negative sepsis, a trend observed in many Indian tertiary care hospitals. The high representation of K. pneumoniae and E. coli in bloodstream infections may be related to urinary tract, abdominal, and catheter-related sources. In contrast, Gram-positive infections, though less frequent, still account for a substantial proportion of cases, particularly in settings involving invasive devices or surgical wounds. The detection of fungal pathogens further highlights the need for heightened vigilance in at-risk populations and consideration of early antifungal coverage in select cases.

Table 2: Distribution of microorganisms isolated from positive blood cultures

For blood culture positivity, PCT demonstrated a strong diagnostic capability with an AUC of 0.87 (95% CI: 0.82–0.92), indicating excellent discriminative power. Using an optimal cut-off value of 2.5 ng/mL, PCT achieved a sensitivity of 84% and specificity of 80%, suggesting that it is highly effective in identifying true positives while maintaining a relatively low false-positive rate. CRP, while still clinically useful, showed a lower diagnostic accuracy with an AUC of 0.74 (95% CI: 0.67–0.80), sensitivity of 72%, and specificity of 68% at a cut-off of 110 mg/L. The combined model incorporating both PCT and CRP yielded the highest performance (AUC = 0.91, 95% CI: 0.87–0.95), with a sensitivity of 91% and specificity of 82%, highlighting the complementary role of these biomarkers when used together.

For cardiovascular dysfunction, PCT again outperformed CRP. The AUC for PCT was 0.85 (95% CI: 0.80–0.90) at a cut-off of 3.0 ng/mL, with sensitivity and specificity values of 83% and 78%, respectively. In contrast, CRP’s diagnostic accuracy for this outcome was lower (AUC = 0.76, 95% CI: 0.70–0.82), with sensitivity of 70% and specificity of 71% at a cut-off of 120 mg/L. This finding underscores the potential role of PCT as a dual-purpose biomarker — not only for early identification of bacteremia but also for recognising patients at risk of sepsis-related cardiac impairment (Table 3).

Clinically, these results suggest that PCT measurement, particularly when combined with CRP, could facilitate earlier and more accurate sepsis diagnosis, expedite targeted antimicrobial initiation, and help identify patients requiring prompt cardiovascular evaluation. The superior performance of the combined biomarker model supports its integration into standard sepsis workup protocols in tertiary care settings.

Table 3: ROC Statistics: Diagnostic PCT, CRP, and their combination in predicting both blood culture positivity and cardiovascular dysfunction in patients with suspected sepsis

Figure 1 depicts the ROC curves comparing PCT, CRP, and a combined PCT+CRP model for identifying blood culture positivity in patients with suspected sepsis. The area AUC for PCT is 0.87 (95% CI: 0.82–0.92), indicating excellent discriminative ability, whereas CRP shows a lower AUC of 0.74 (95% CI: 0.67–0.80), consistent with only fair to good discrimination. The combined model achieves an AUC of 0.91 (95% CI: 0.87–0.95), which reflects near-outstanding performance and demonstrates additive value when both biomarkers are used together.

At the prespecified operating points, PCT with a cut-off of 2.5 ng/mL yields a sensitivity of 84% and specificity of 80% (Youden index 0.64), while CRP at 110 mg/L provides a sensitivity of 72% and specificity of 68% (Youden index 0.40). The combined model improves sensitivity to 91% and specificity to 82% (Youden index 0.73). These thresholds balance false positives and false negatives and illustrate how PCT alone already performs well, with further gains when both markers are combined.

Likelihood ratios help translate these operating points into bedside decision-making. For blood culture positivity, PCT has a positive likelihood ratio (LR+) of approximately 4.2 and a negative likelihood ratio (LR−) of 0.20, compared with CRP (LR+ ≈ 2.25; LR− ≈ 0.41). The combined model shows the strongest shifts in probability (LR+ ≈ 5.06; LR− ≈ 0.11), meaning a positive combined result substantially increases the post-test probability of bacteremia, while a negative result markedly lowers it.

Using the observed prevalence of culture positivity in this cohort (43.8%), the estimated predictive values at the chosen thresholds are as follows: PCT PPV ≈ 76.6% and NPV ≈ 86.5%; CRP PPV ≈ 63.7% and NPV ≈ 75.7%; combined model PPV ≈ 79.8% and NPV ≈ 92.1%. Thus, the combined approach offers the highest reassurance when tests are negative and the greatest confidence when tests are positive.

Clinically, these curves highlight the value of measuring PCT early, with CRP providing complementary information. Higher sensitivity is desirable when the priority is to avoid missed infections, while higher specificity is helpful to limit unnecessary broad-spectrum antibiotics. The combined model may therefore be most useful at initial triage to guide empiric therapy while awaiting cultures. As with all ROC-based analyses, performance can vary with disease prevalence and patient mix; external validation and assessment of calibration are recommended before adopting fixed thresholds in different settings.

Figure 1 illustrates the ROC curves for PCT, CRP, and their combination in predicting blood culture positivity. The PCT curve demonstrates the highest area under the curve (AUC = 0.87), indicating superior diagnostic accuracy compared to CRP (AUC = 0.74). The combined biomarker model achieved the best performance (AUC = 0.91), suggesting that using both markers together enhances predictive capability. The diagonal line represents the line of no-discrimination (AUC = 0.5).

This prospective study explored the diagnostic utility of PCT and CRP in predicting blood culture positivity and cardiovascular dysfunction in patients with clinically suspected sepsis in a tertiary care hospital. The results indicate that PCT demonstrated superior performance over CRP in both microbiological and cardiac outcome prediction. Furthermore, combining both biomarkers enhanced diagnostic accuracy, offering a practical and potentially impactful approach to sepsis evaluation in clinical settings.

Microbiological Findings and Clinical Relevance

The blood culture positivity rate in our cohort was 43.8%, which is consistent with prior reports from Indian and other Asian tertiary care settings, where positivity rates generally range between 35% and 50% [4, 24]. The predominance of Gram-negative bacilli, particularly Klebsiella pneumoniae and Escherichia coli, mirrors the microbial epidemiology described in several multi-centre studies [25, 26]. Both organisms are notorious for harbouring extended-spectrum β-lactamases (ESBLs) and carbapenem resistance, posing substantial treatment challenges [26].

The relatively high proportion of Gram-positive isolates (38%), led by Staphylococcus aureus and Enterococcus faecalis, underscores the dual epidemiological burden in sepsis, where both Gram-negative and Gram-positive organisms remain clinically significant. This aligns with European and North American ICU surveillance data that also report mixed microbial patterns [27]. Fungal pathogens, though less frequent (5.4%), were represented entirely by Candida species, which are known to be associated with high morbidity, particularly in immunocompromised or long-stay ICU patients [28]. This finding supports targeted fungal screening and empiric therapy consideration in high-risk subgroups.

Biomarker Performance for Predicting Culture Positivity

PCT’s superior diagnostic accuracy (AUC 0.87) compared to CRP (AUC 0.74) reinforces the growing body of evidence supporting its role in early sepsis diagnosis [10, 11]. PCT’s pathophysiological advantage lies in its rapid induction by bacterial endotoxins and pro-inflammatory cytokines, with levels rising within 4–6 hours and correlating with bacterial load [8]. In contrast, CRP synthesis is driven primarily by interleukin-6 and other inflammatory mediators, making it sensitive but less specific, as it is elevated in many non-infectious conditions including trauma, burns, and autoimmune diseases [13].

The combined biomarker model (AUC 0.91) demonstrated the highest diagnostic accuracy. This synergy can be attributed to their complementary kinetics — PCT’s rapid rise for early bacterial recognition and CRP’s robust but slower inflammatory response. Prior studies have shown that integrating multiple biomarkers can significantly improve early sepsis detection, reduce diagnostic uncertainty, and guide empirical antimicrobial selection [23, 29].

Cardiovascular Dysfunction in Sepsis and Biomarker Associations

Cardiovascular dysfunction was detected in nearly half of the study population (49%), consistent with the reported prevalence of sepsis-induced myocardial dysfunction (SIMD), which ranges from 40–50% [18, 21]. The strong correlation between elevated PCT levels and reduced LVEF or elevated NT-proBNP suggests that systemic inflammatory burden and myocardial injury share overlapping pathophysiological mechanisms. Experimental data indicate that pro-inflammatory cytokines such as TNF-α and IL-1β, which also stimulate PCT production, can cause direct myocardial depression, mitochondrial dysfunction, and nitric oxide overproduction [19, 20].

CRP, while showing a weaker association than PCT, also correlated with cardiac dysfunction, supporting prior findings that CRP levels may reflect the degree of systemic inflammation and endothelial activation in sepsis [22]. This cardiac–biomarker relationship highlights the potential role of early biomarker assessment not only in diagnosing sepsis but also in identifying patients at risk of septic cardiomyopathy, enabling timely echocardiographic monitoring and cardiology consultation.

Clinical Implications

From a clinical standpoint, the findings suggest that early measurement of PCT and CRP in suspected sepsis could provide a rapid, cost-effective, and accessible tool for identifying patients with high likelihood of bacteremia and concurrent cardiovascular involvement. In resource-limited settings, where access to rapid molecular diagnostics or continuous cardiac monitoring may be constrained, this approach could help prioritise patients for urgent interventions. The high negative predictive value of the combined biomarker model (92.1%) also suggests its utility in ruling out severe infection in low-probability cases, potentially reducing unnecessary antimicrobial use.

Integration of biomarker testing into sepsis bundles could shorten the time to appropriate therapy, improve antimicrobial stewardship, and prompt early cardiovascular assessment, potentially mitigating downstream complications such as septic shock and multi-organ dysfunction.

Strengths and Limitations

The major strengths of this study include its prospective design, standardised timing of sample collection before antibiotic initiation, and integration of microbiology, biochemistry, and cardiology evaluations in the same patient cohort. These factors enhance internal validity and clinical relevance.

However, there are some limitations. Being a single-centre study may limit generalisability across regions with different pathogen prevalence and resistance patterns. Excluding patients who had received antibiotics within 48 hours may have underestimated the proportion of culture-negative sepsis. Additionally, biomarker levels were measured only at baseline; serial measurements could have provided insights into prognostic trajectories and response to therapy. Finally, echocardiographic assessment was performed within the first 24 hours only, so dynamic changes in cardiac function over time were not captured.

Future Directions

Future research should evaluate the performance of combined PCT–CRP testing in larger, multi-centre cohorts and assess its integration with other emerging biomarkers such as presepsin, mid-regional pro-adrenomedullin (MR-proADM), and soluble triggering receptor expressed on myeloid cells-1 (sTREM-1). Longitudinal studies could explore the utility of serial biomarker measurements for monitoring therapeutic response and predicting long-term outcomes. Furthermore, cost-effectiveness analyses are essential to determine the economic feasibility of routine dual-biomarker testing in sepsis protocols, especially in low- and middle-income countries.

In this prospective study, procalcitonin demonstrated superior diagnostic accuracy compared to C-reactive protein for predicting both blood culture positivity and cardiovascular dysfunction in patients with suspected sepsis. The combination of these two biomarkers further enhanced sensitivity and specificity, providing a valuable adjunct to standard clinical and microbiological assessments. Cardiovascular dysfunction was common in this cohort and showed a strong association with elevated biomarker levels, underscoring the interrelationship between systemic inflammation and myocardial impairment in sepsis.

The integration of PCT and CRP testing into early sepsis evaluation could facilitate prompt risk stratification, guide timely antimicrobial therapy, and trigger early cardiac assessment. Such an approach has the potential to improve patient outcomes, especially in high-burden tertiary care settings. Multicentre studies and cost-effectiveness analyses are warranted to validate these findings and support the incorporation of dual-biomarker strategies into routine sepsis management protocols.

Acknowledgements

The authors gratefully acknowledge the support of the Departments of Microbiology, Biochemistry, and Cardiology at Mahatma Gandhi Memorial (MGM) Hospital, Warangal, for their assistance in patient recruitment, sample processing, and data collection. The authors also thank the technical staff for their contributions to laboratory assays and echocardiographic evaluations. Special appreciation is extended to the patients and their families for their participation in this study.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Conflict of Interest

The authors declare that there is no conflict of interest regarding the publication of this study.

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