Neutrophil-to-lymphocyte ratio as marker of organ... : Journal of Clinical and Scientific Research (2024)

INTRODUCTION

Sepsis is a life-threatening acute inflammatory condition involving a complex and dysregulated host immune response to infection and impairment of microvasculature. Despite major advances in diagnostic and therapeutic arsenal, it remains a major challenge in both the developed and developing worlds. Sepsis and septic shock remain one of the leading causes of death worldwide, with the majority of the burden falling on critically ill patients.^[1,2] Sepsis has been observed in about 49 million patients worldwide, with 19.7% of total deaths and an in-hospital mortality rate ranging from 20% - 41%.^[3,4]

The revised definition of sepsis by the Third International Consensus Definitions (2016) for Sepsis and Septic Shock (Sepsis-3) describes it as a ‘life-threatening organ dysfunction caused by dysregulated host responses to infection’.^[5] However, the defined mechanisms of systemic organ dysfunction due to sepsis are still less clearly understood. The currently available scoring systems, are useful in the evaluation of organ dysfunction over time in patients with sepsis and have been established as clinically useful indices of severity and prognosis.^[6] Of these, the sequential organ failure assessment (SOFA) score incorporates haematological (platelet count), hepatobiliary (bilirubin levels), respiratory, cardiovascular, renal and central nervous system impairment assessment.^[7] The score ranges from 0 to 24, and the maximum score is designated for severe organ dysfunction related to sepsis.

Patients with sepsis need to be identified before the onset of organ dysfunction. This requires good point-of-care testing. Since there is no gold-standard diagnostic marker for sepsis, conventional and certain novel biomarkers are applied that may help predict responses to treatment and prognosticate survival. Various such biomarkers include C-reactive protein, interleukin-6 and procalcitonin. These are widely used in diagnosing and monitoring critically ill patients with sepsis. However, the cost is prohibitive, and the availability is limited in India and other developing countries. The neutrophil-to-lymphocyte ratio (NLR) is one investigation that has the potential to circumvent these limitations. In an infection, the host immune response usually demonstrates an increment in the neutrophil count and a decrement in the lymphocytes. The underlying pathophysiology of this process can be explained by a stress-related rise in cortisol and catecholamine levels leading to increased neutrophils and decreased leucocyte count or sepsis-induced leucocyte apoptosis.^[8] Thus, we carried out this study to observe the role of NLR as a marker for organ dysfunction severity and prognosis in critically ill patients. Thus, this study was done to identify the role of NLR in predicting organ dysfunction severity and prognosis in patients with sepsis requiring admission to an intensive care unit (ICU).

MATERIAL AND METHODS

We conducted an observational study in our tertiary-level hospital for 6 months, from January to June 2019. Consecutive patients with sepsis were enrolled from the ICU of the department of general medicine. Sepsis was defined as per the guidelines of Sepsis-3 as suspected (or documented) infection and an acute increase in ≥2 sepsis-related SOFA points.^[5] Septic shock was defined as sepsis plus vasopressor therapy needed to maintain the mean arterial pressure at ≥65 mmHg and serum lactate >2.0 mmol/L despite adequate fluid resuscitation. All of the sepsis patients were investigated and managed as per the specific disease management protocols.

Inclusion criteria: adults at least 18 years of age, having sepsis (as defined by the standard criteria above) and with ≥1 of the following infections: community-acquired pneumonia, hospital-acquired pneumonia, urinary tract infection, pyelonephritis, surgical-site infection or intra-abdominal infection. Exclusion criteria: patients with age <18 years, known immunocompromised states, on chemo- or radiotherapy, pregnant females and individuals on steroids were excluded. Furthermore, patients/next to kin who were not willing to participate were not included in the study.

This study was approved by the Institutional Review Board (vide number RC-05-Feb-19). Written informed consent was obtained from the patients or their first-degree relatives (in case of patients’ inability). No intrusions or changes were made in the routine management of the patient. Participants (or first-degree relatives) were assured that confidentiality of personal data would be maintained at every possible level.

Patients giving positive consent and fulfilling the inclusion criteria with sepsis were included, and the admission NLR was calculated using absolute neutrophil and lymphocyte counts using Beckman Coulter LH 780, automated haematology analyser (Beckman Coulter, Inc. Miami, FL, USA). The SOFA scores were evaluated at the time of admission to the ICU.

Other investigations supporting the diagnosis, such as blood or urine culture, chest X-ray and abdominal ultrasound, were also noted. The patients were then followed until the primary outcome, i.e., discharge or mortality.

Statistical analysis

All data were first entered into a Microsoft Excel 2019 (Microsoft Corporation, New Mexico, the Redmond, USA). Data are expressed as mean ± standard deviation, numbers and percentages. Variables were compared using Fisher’s exact test, Student t-test and Mann–Whitney U test as appropriate. Correlation association was tested using the Pearson ‘r’ correlation analysis, numbers and percentages. A P- value <0.05 was considered statistically significant. Statistical analysis was done using Statistical Package for Social Sciences (SPSS) version 28 (IBM Corporation, New York, USA).

RESULTS

Sixty ICU patients with sepsis were identified after fulfilling the inclusion criteria; however, three patients turned out to be immunocompromised, and two refused to be enrolled. Hence, 55 patients were considered for analysis. Of these, 31 were males. Pneumonia (38.2%) was the leading cause of sepsis, followed by urinary tract infection (25.5%), surgical (20.0%) and intra-abdominal causes (16.3%).

Eighteen (32.7%) patients in the study cohort developed septic shock as per the defined definition, and we studied various laboratory parameters in patients with sepsis only and sepsis with septic shock (Table 1). The mean haemoglobin, platelet count and total leucocyte count were lower in patients with septic shock. However, the NLR ratio (8.96 ± 2.80, P = 0.03) and SOFA score (9.94 ± 3.78) average values were significantly higher amongst these patients. Furthermore, the mortality rate was 50% in patients with septic shock, which was comparatively higher than the rate in patients with sepsis alone (35.1%).

A positive correlation was observed between SOFA score and NLR (Figure 1, Tables 2a, 2b and 2c) in all patients (r = 0.5584, P < 0.001); patients with sepsis only (r = 0.4821, P = 0.002); and patients with sepsis and shock (r = 0.6321, P = 0.004).

Similarly, A positive correlation was noted between NLR an hospital stay duration (r = 0.1581,P = 0.24) but this was statistically insignificant (Figures 2a, 2b and 2c).

In the total population, mean NLR was significantly higher among non-survivors, compared to survivors (9.17 vs. 7.09; P = 0.0054) (Table 3).

DISCUSSION

In this study, ICU patients with sepsis were included and evaluated for organ dysfunction severity and prognosis correlation with NLR. Our study cohort has a higher number of male patients, which indicates more incidence of sepsis in the male population. A similar study on 3902 individuals demonstrated that the male population suffers more from sepsis than its female counterpart; however, female individuals had more risk of mortality due to sepsis.^[9]

When patients with sepsis and septic shock were compared, the mean value of total platelet count was considerably lower in the presence of septic shock. This can be explained by the sepsis-induced bone marrow suppression, peripheral destruction and haemophagocytic histiocytosis.^[10] In a case–control study on sepsis patients, the platelet count was found to be lower in patients with severe sepsis, which is similar to our finding.^[10] The study also concluded that higher platelet distribution width can be associated with more mortality in sepsis. Another study^[11] conducted in 5537 sepsis patients, showed that raised platelet-to-lymphocyte ratio values at hospital admission can predict higher mortality.

Similar to the platelet count, the average total leucocyte count in patients with severe disease (septic shock) was also lower, when compared with patients with sepsis only. This finding was consistent with other studies including similar patient cohorts.^[8,12] Being a complex infirmity, patients with sepsis and septic shock can have a variable leucocyte count, and plenty of these individuals may demonstrate a normal leucocyte count.^[13] To overcome this difficulty, NLR has emerged as a newer tool to identify sepsis severity and prognosis, and recent literature has demonstrated positive results in this field. A study^[14] showed that the NLR was an easily measurable parameter from a complete blood count for determining prognosis during ICU follow-up of the patient, and it could be used routinely in daily clinical practice. In addition, another study^[15] found that NLR combined with a SOFA score can predict 28-day mortality better than NLR and SOFA score alone.

We assessed NLR with sepsis-related organ dysfunction severity (i.e., SOFA score) and with hospital stay duration and mortality. The correlation between NLR and SOFA score was positive and statistically significant, with a higher correlation coefficient value in patients with septic shock. Instead of having a lower average total leucocyte count, the NLR was raised amongst septic shock patients, which depicts the inefficacy of the leucocyte count in identifying severe disease. A recent study^[8] on 114 ICU-admitted patients also found a lower total leucocyte count in severe sepsis; however, the NLR was significantly higher in this patient group. This finding supports the prompt measurement of NLR in sepsis patients rather than merely relying on total leucocyte count.

The NLR association with hospital stay duration demonstrated a positive correlation, i.e. a higher ratio of patients having longer hospital stays. Similarly, individuals which was higher ratio had a higher risk of in-hospital mortality, with a statistically significant. Studies^[9,12] have demonstrated similar results, stating NLR as a prognosis-predicting marker. A study^[16] additionally demonstrated that an increment of one point in the NLR can raise mortality by 5%. Similarly, another study^[17] had assessed 373 critically ill patients and concluded that the NLR can direct emergency department physicians for early interventions. Our study could not identify a statistically significant association between in-hospital mortality and NLR for patients with septic shock, which can be explained by the multifactorial process of mortality in the presence of shock. In a study^[18] mortality of septic shock was dependent on hepatic or respiratory dysfunction, and the neutrophil count at admission was found to be insignificant. Similarly, in studies on septic shock patients, net fluid balance and cardiac function,^[19] and hyperlactataemia^[20] were found to be as an independent marker of mortality.^[19,20]

One major limitation of this study is the small sample size, which can be one more reason for the statistically insignificant correlation between NLR and in-hospital mortality for septic shock patients. Second, it was a single-centre observational study; hence, results should be validated by further multicenter, prospective studies with a larger sample size. In addition, NLR and SOFA scores were calculated only at the time of admission in the ICU, which could be inferior to sequential evaluation.

On the basis of our study results, we recommend NLR measurement for delineating the organ dysfunction severity in sepsis, which is an easy-to-calculate, cost-effective and readily available tool. As results demonstrated, the total leucocyte count is less reliable for identifying severity and may have variable values. Furthermore, patients with higher NLR values should be managed more aggressively to avoid a longer hospital stay and mortality.

In conclusion, the study demonstrated that NLR and SOFA score have a positive statistically significant correlation, which concludes that NLR measurement at admission in sepsis patients can accurately identify disease-related organ dysfunction severity. The higher ratio is also associated with a longer hospital stay and poor prognosis. The total leucocyte count was inferior to the NLR in correctly delineating severe sepsis, thus having questionable reliability. Easy availability and quick result calculation make NLR a good tool for fast-paced ICU settings.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

REFERENCES