European Journal of Cardiovascular Medicine

Sepsis is a serious kind of life-threatening complications arising out of extreme reaction induced in the body to fight infection¹. The chemicals released into the blood stream in the process to fight infection triggers inflammation and are responsible for a cascade of changes that can damage multiple organ system^{2, 3.} Most often; it starts in the lung, urinary tract, skin, gastrointestinal tract, brain and other organ resulting to the death of the patient ⁴. It can affect anyone at any age however people with altered immune system and chronic illness are more susceptible to sepsis. Clinical practice shows that patients with blood stream infection caused by bacterial infection have a very high probability of developing sepsis and septic shock within a short period of time ^5,6. Despite the current advances in medical science, technology and practice it has been observed that mortality rate in sepsis remains too high and hence it is regarded as a global health problem^{7,8,9. Moreover}, patients surviving sepsis often experiences long term physical, psychological and cognitive impairment known as post sepsis syndrome, diminishing quality of life and productivity ¹⁰ . The global sepsis mortality rate in 2017 was 19.7% accounting for a total of 11 million    deaths with 1 in every 5 deaths being sepsis related. In India, the sepsis incidence is 540-640 per 1 Lakh population and the estimated total sepsis burden is 89.6 Lakhs with a mortality of 25-30% ^11. Therefore, the early identification of the severity of infection and timely administration of standardized treatment is of higher priority in the emergency department ¹², which can significantly improve the prognosis of patients with sepsis.

The paradigm of sepsis pathogenesis has evolved over the time and different approaches have been tried. Investigators often used different clinical parameter, assessment and scoring system for diagnosis, prognosis and monitoring. Routine blood cultures are the gold- standard for diagnosis of blood stream infection along with other clinical conditions such as body temperature, blood pressure, heart rate, respiratory rate etc., but such practices suffer from the limitations such as accuracy and promptness. The clinical signs and symptoms associated with sepsis usually overlap with other SIRS, so there is a need for effective indicator to facilitate the identification and distinguish sepsis from other non-infectious SIRS¹³.  In recent years, the level of serum inflammatory factors in the blood such as C - reactive protein(C-RP), Leucocytes cell count, Cytokines [Inter leukin-6 (IL-6), Tumour necrosis factor (TNF)] etc. have been applied in diagnosis of sepsis and determination of the disease, but lacking of their specificity ¹⁴ has generated search for more specific Bio-marker. In recent time Pro- calcitonin (PCT) and Neutrophil to Lymphocytes count ratio (NLR) etc. have been evolved as useful Bio-marker to differentiate sepsis from other non-infectious causes.

Pro-calcitonin is a peptide precursor of calcitonin and is a part of the inflammatory cascade in sepsis.PCT is produced by Para follicular cells (C- cells) of the thyroid and by the neuroendocrine cells of the lung and the intestine. PCT originate from the calcitonin -1 (CALC-1) gene on chromosome -11.PCT producing CALAC-1 gene is increased in multiple extra thyroid tissues throughout the body in bacterial infection. In the absence of infection, the extra thyroidal transcription of CALAC -1 gene is suppressed. Therefore, PCT detected in the plasma during infection is not produced by C-cells of the thyroid rather by the neuroendocrine cells in the lungs or intestine^15,16. Pro-calcitonin level tends to be elevated in bacterial infection where as they are depressed in viral infection and high  PCT has been  known to predict bacteraemia¹⁷.Pro-calcitonin is detectable in the serum within 4 hours and has a half- life of 22-26 hours ¹⁸ while, Peak level occurs between 12 and 48 hours ¹⁹.However, PCT levels may be elevated in patients who do not have sepsis, with levels between 2-10 ng/ml seen in patients with conditions such as autoimmune disorders, trauma, cardiac arrest, surgery, Burns and pancreatitis and other non-infectious diseases ²⁰. Serum PCT level reflects the severity of inflammation; higher level associated with more severe disease and declining level with recovery of illness ²¹. It has been established that PCT provides information in early stages of sepsis as well as during antimicrobial treatment and can be useful in reduction of unnecessary antimicrobial therapy²². Recent study reported from China concluded that PCT has a better diagnostic value than C-RP and white blood count (WBC) when differentiate SIRS patient with and without infection²³, while in an another study it has been observed that there was no statically significant difference in PCT level in sepsis group in compared to the group with other non-inflammatory conditions such as trauma, stroke, gastrointestinal perforation bleeding, cardiac arrest etc.^24,39.

 It is now an established fact that inflammation and immune response plays a pivotal role in the occurrence and progression of sepsis²⁵. One of the responses of immune system against infection is increase of Neutrophil and consequently decreases in Lymphocytes number. This is due to change in the dynamics and regulation of apoptosis in a state of systematic inflammation when compared with non -inflammatory state. Delay of Neutrophila apoptosis, contrarily increase of Lymphocyte apoptosis as seen in systematic inflammation and stress was first reported by Zahorec et al.²⁶, which is the related hypothesis of high Neutrophil to Lymphocytes count ratio (NLR) in sepsis and thus it represents a calculated parameter derived from total blood count. It has been observed that activated neutrophils can release inflammatory cytokines and can cause dysfunction of the organs by damaging tissues of organ system. Contrarily, apoptosis of Lymphocytes may supress the activity of the immune system and the patient becomes more susceptible for further infection and consequently inflammatory reaction^26,27.

A retrospective cohort study showed that NLR could be used as a predictor of in-hospital mortality in sepsis patient²⁸. Some other studies have shown that NLR could accurately reflect the severity of sepsis²⁹.

In this background, this retrospective study was conducted to compare the usefulness of NLR and PCT in evaluation of severity of sepsis and to correlate both the sepsis indicator with acute physiology and chronic health evaluation (APACHE-II) scoring system, a standardized classification of disease severity and thus to provide a basis for early assessment of the severity of sepsis and prognosis there-of. NLR is a calculated parameter, economical, simple, and accurately reflects the activation and regulation of inflammation in the body.

This retrospective study was conducted from the data available at the records of Assam Medical College Dibrugharh during the period of January 2024 to December 2024.The study population were adult patients above the age of 18 years admitted in the multidisciplinary intensive care unit (ICU) with sepsis. Pregnant females were excluded from this study. The sample size of study population was 80.

Convenient sampling was done by collecting different variables and information like presence of Neutrophils, Lymphocytes, PCT, APACHE-II score, total WBC count, sex, age, patient’s therapy etc. The patients were grouped in to sepsis and severe sepsis on the basis of clinical signs.

Total 80 numbers of patients were included in the study comprising patients with age group from >18 years to 77 years. The patients were grouped into sepsis and severe sepsis. The most common age group of patients suffering from sepsis was 51-60 years out of which 27.5% patient suffered from sepsis and 40 % of the patients suffered from severe sepsis followed by patients with aged >60 years where 25% were under sepsis and 22.5% were under severe sepsis group. The mean age of the patients according to the group of severity of disease are as 51.30±13.00 in sepsis group and 54.45±10.01 in severe sepsis group.

Table–1: Comparison of parameter between sepsis and severe sepsis group.

Table-1 depicts that he means APACHE II score were (14.45±1.84) in sepsis group and (26.10±5.44) in the severe sepsis group stating higher APACHE- II in severe sepsis compared to the sepsis group with p<0.001 implying the findings were statistically significant. Similarly, the mean Neutrophil was (972.20±11.89) in sepsis group and (73.95±10.98) in severe sepsis group. No significant difference between the both groups have been seen as evidenced by p=0.496. Observed mean lymphocyte count was (4.63±1.44) in sepsis group and (3.23±0.97) in severe sepsis group. Mean lymphocyte was found to be lower in severe sepsis group compared to the sepsis group and was statistically significant (p<0.001). The results of NLR and PCT show a significant association with severity of disease. The mean NLR was (16.98 ±7.26) in sepsis group and (25.11±7.63) in severe sepsis group while the mean PCT was (9.02±1.73) in patients with sepsis group and (72.65±13.59) in severe sepsis group. Higher level of NLR and PCT in severe sepsis group with p<0.001 implies that the data are statistically significant and there exists a close association with the severity of disease.

Correlation of NLR and PCT with APACHE-II score were calculated by using Spearman’s correlation test and observed significant positive correlation (Table -2) in both sepsis and severe sepsis group, however the correlation of both the indicator was stronger in severe sepsis group compared to that of the sepsis group.

Table–2: Correlation between APACHE II Score with NLR

Figure 5.22.1-Combined ROC for NLR and PCT

Table -3: Comparison of ROC values of NLR vs PCT.

Table-4: Combined ROC values of NLR and PCT

PPV-Positive Predictive Value

NPV-Negative Predictive Value

The Receiver Operating Characteristic (ROC) analysis was conducted to evaluate the diagnostic accuracy of Neutrophil-to-Lymphocyte Ratio (NLR) and Pro-calcitonin (PCT) in differentiating sepsis from severe sepsis. The optimal cut-off points (COP) were determined as per Youden Index, and both the parameter viz. sensitivity and specificity were calculated based on the COP (Table – 3).

The AUC (Area Under the Curve) for NLR was 0.826, with a 95% confidence interval ranging from 0.734 to 0.918 and the obtained optimal cut-off (COP) is 17.92 yielding a sensitivity of 77.5% and a specificity of 65%. The Positive Predictive Value (PPV) was 68.89%, and the Negative Predictive Value (NPV) was 74.29%, with an overall accuracy of 71.25%. This suggests that NLR has a moderate discriminative ability in identifying severe sepsis.

While the AUC of Pro-calcitonin (PCT) was 0.963, with a 95% confidence interval ranging from 0.917 to 0.995 and the optimal PCT cut-off (based on Youden’s Index) is 9.48 ng/ml demonstrating a higher sensitivity of 98.5% and a specificity of 62.5%. The PPV and NPV were 72.7% and 90%, respectively, with an accuracy of 81.3%. These findings indicate that PCT has a stronger ability to identify severe sepsis due to its high sensitivity, making it a useful biomarker in early sepsis diagnosis. (Wheather this statement as given in ur thesis is correct or not discuss it)

In comparison the AUC of PCT is higher than NLR (0.963 Vs. 0.8), Sensitivity of PCT (98.5)> NLR (77.5) and Specificity of NLR (65)>PCT (62.5). The AUC (0.975) and Specificity (82.5) of the combined ROC of PCT and NLR is higher than the PCT and NLR alone. Though the Combined ROC yielded higher Sensitivity (97.5) than that of NLR (77.5), butit is slightly less than that of the PCT (98.5) alone.

The present study revealed that PCT levels (9.02 ± 1.73 and 72.65 ± 13.59; p<0.001 in sepsis and severe sepsis group respectively) as well as NLR values (16.98 ± 7.26 and 25.11 ± 7.63; p<0.001 in sepsis and severe sepsis group respectively) were significantly higher in patients with severe sepsis than in sepsis group and observed that patient with higher value of PCT and NLR had increased risk of sepsis mortality. This suggests that the severity of disease with blood stream infection sepsis can be reflected by the both NLR and PCT effectively. This finding is in consistent with most of the previous studies that had reported close association of elevated NLR and PCT with the poor outcome in septic patients^{30, 34,35,36,37,38} and further supports their predictive and prognostic potential in dealing with the severity of the disease.

Acute Physiology and chronic health evaluation (APACHE-II) scoring system is a recognized measure of the severity of disease and to predict outcome of critically ill patients ³⁹. The significant positive correlation of NLR, PCT, and APACHE II scores as observed in our investigation revealed that both the biomarker is strongly correlation with sepsis severity (Table- ) which may make them potentially reliable marker. Patients with higher NLR and PCT values exhibited elevated APACHE II scores, indicating higher mortality risk, though the correlation between NLR and APACHE II score was not as strong as the correlation between PCT and APACHE II score. PCT appears to be more effective than NLR for assessing severity of sepsis as correlation of PCT (sepsis group r=0.323, p=0.042; severe sepsis group r=0.615 and p=0.001) > correlation of NLR (sepsis group r=0.230, p=0.153; severe sepsis group r=0.504, p=0.001). The present results are similar to many studies that identified stronger correlation of PCT and sepsis than NLR while few other studies found substantial correlation between NLR and Sepsis ^31,40,41. The correlations further suggest that both PCT and NLR, in align with the APACHE II score can predict and prognoses sepsis independently as well as in combinations.

Analysis of the ROC curve shows that both the indicator possesses significant area under ROC curve (AUC) which signifies that values of both the parameters effectively useful in prognosis and diagnosis of bacterial sepsis, however the efficacy of PCT is better than NLR being AUC of PCT is greater than AUC of NLR (0.963 Vs 0.826).

 In a retrospective study, Dragoescu et al.³⁰ investigated the predictive value of NLR in a cohort of114 septic patients, including 38 patients who developed septic shock and it has been found that NLR had a good sensitivity of 47% and specificity of 78% for predicting the occurrence of septic shock, with an cut-off value of 10.42 and a significant AUC of 0.631. In their study De Jager et al.³⁷ also   observed a “cut-off value of 10.0, sensitivity 77.2% and specificity   63.0 % in diagnosing sepsis”. Study of Cai et al.³⁸ found “NLR cut off > 10.29 for accurate prediction of critical bacterial sepsis”. Our present observed optimal cut off value of ROC curve with respect to NLR is 17.92, having a good sensitivity (77.5%) and specificity (65%) which indicates presence of severe sepsis and the results are in line with the earlier observations^30,37.

As far as the AUC inspection of PTC is concerned, it is (0.963), in the interval from 0.917 to 0.995 at 95% confidence interval with an optimal PCT cut-off (based on Youden’s Index) of 9.48 ng/ml. The sensitivity, specificity, PPV, NPV and accuracy were 98.5%, 62.5 %, and 72.7%, 90% and 81.3 % respectively. This suggests that PCT shows a good predictive value and in comparison, to NLR, PCT may be considered as a better performer for predicting the severity of bacterial sepsis as the AUC as well as sensitivity of PCT recorded higher value than that of NLR (AUC =0.963 vs 0.826 and Sensitivity= 98.5 Vs 77.5), which is similar to some earlier observations³⁵.

The slight deviation of the COP of NLR and PCT as observed in our present study may be due to difference in study design (retrospective Study), sample size, different source of infection and different time point of assessment.

PCT has been widely used in diagnosis and treatment of sepsis because of the high sensitivity, accuracy, and rapidity. It provides important information in early stages of sepsis as well as during antimicrobial treatment ^42,43,44,45. PCT level>2.00ng/ml are highly suggestive of systemic bacterial infection or sepsis⁴⁷ and is detectable in serum within 4 hours of infection¹⁸. Despite its superior performance compared to some traditional biomarker, PCT measurement is not sufficiently sensitive or specific to serve as a stand-alone test for diagnosis of sepsis⁴⁸.PCT levels may be elevated in patients between (2-10 ng /ml) who do not have sepsis but with the conditions such as auto immune disorders, trauma, cardiac arrest, surgery, burns and pancreatitis²⁰. This implies that PCT has limiting specificity and may not accurately identify the actual cause of sepsis or may be falsely elevated in other conditions. Thus, independent detection of serum PCT is affected by various factors and to diagnose invasive bacterial infection and their severity assessment, PCT level alone may not be enough because of the challenge in differentiating microbial and non-microbial infection cases⁴⁹.

 NLR is comparatively a new inflammatory indicator and can be used for prognosis of severity assessment. It is an economic and easily available parameter that can be derived from complete blood cell count. Higher NLR values indicates un- favourable prognosis in the septic patient ^28,29. According to some study NLR is a more convenient marker for infection with high septicity (83.9%) but moderate sensitivity for diagnosing septicaemia in critically ill patients ^{50 ,51}.  Contrarily, some other study states that elevated NLR level may not always diagnose sepsis; as it may be seen in many other conditions including age, medication, chronic disease like coronary heart disease, stroke, diabetes, obesity, cancer of solid organs, anaemia and stress etc.^52,53 . Yet, it is found to be useful to assess the severity of the disease with features of systemic inflammatory response as the change in NLR values may be a valuable prognostic marker of sepsis “54^.

Though the PCT level and NLR values seems to be very useful for prognosis of sepsis but are not sufficient enough due to the limiting factors such as sensitivity, septicity as well as complexity of sepsis itself. Zhang et al.⁵⁵ evaluated multiple indicators and found that the “combinations of any two bio-indicators can improve the sensitivity and specificity for diagnosis of sepsis”. The combined AUC (0.975) in our observation is found to be superior to the individual AUCs of NLR (0.826) and PCT (0.963). Though the combined sensitivity is slightly less than of PCT (97.5Vs 98.5); yet the combination demonstrated an improved diagnostic performance with better specificity (82.5) and overall accuracy in differentiating sepsis from severe sepsis. The results imply that compared to NLR and PCT levels alone their combination may yield a better result in therapeutic decision making and add more accurate information about screening, diagnosis and risk stratification and response monitoring to the given therapy.

The study concluded that both PCT and NLR can be used for early diagnosis of bacterial sepsis however, the individual performance of PCT is better than NLR. Though NLR is a simple and readily available indicator specific enough to prognoses sepsis and severe sepsis but the combination of these two markers may be more valuable in the early diagnosis and prognostic evaluation of sepsis.

Limitations:

Small sample size: The sample size of the study is relatively small, stem from a single cantered study. A larger cohort study is needed to validate findings across diverse populations.

Retrospective study: Being a retrospective study, susceptible to some inherent disadvantages viz. prone to selection bias as well as having incomplete documents or clinical information.

Single-centre study: The results may be extrapolated or may not be generalizable to other populations in different healthcare settings.

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