Association Between ICU admission (Neutrophil + Monocyte)/Lymphocyte Ratio And 30-Day Mortality in Patients with Sepsis: A Retrospective Study from MIMIC-IV

Background: Sepsis is an important public health issue, and it is urgent to develop valuable indicators to predict the prognosis of sepsis. Our study aims to assess the predictive value of ICU admission (Neutrophil + Monocyte)/lymphocyte ratio (NMLR) on the 30-day mortality of sepsis patients. Methods: A retrospective analysis was conducted in septic patients, and the data were collected from Medical Information Mart for Intensive Care IV (MIMIC-IV). Univariate and multivariate Cox regression analyses were conducted to investigate the relation between ICU admission NMLR and 30-day mortality. Restricted cubic spline (RCS) was performed to determine the optimum cut-off value of ICU admission NMLR. Survival outcomes of the two groups with different ICU admission NMLR levels were estimated using the Kaplan-Meier method and compared by the log-rank test. Results: Finally, 7292 patients were recruited in the study, of which 1601 died within 30 days of discharge. The non-survival group had higher ICU admission NMLR values than patients in the survival group (12.24 [6.44–23.67] vs. 8.71 [4.81–16.26], P < 0.001). Univariate and multivariate Cox regression analysis demonstrated that ICU admission NMLR was an independent prognostic predictor on 30-day mortality (Univariate: P < 0.001; multivariate: P=0.011). The RCS model demonstrated the upturn and non-linear relationship between ICU admission NMLR and 30-day mortality (Nonlinearity: P=0.0124). According to the KM curve analysis,30-day survival was worse in the higher ICU admission NMLR group than that in the lower ICU admission NMLR group (Log rank test, P<0.0001). Conclusion: The elevated ICU admission NMLR level is an independent risk factor for high 30-day mortality in patients with sepsis.


Background
Sepsis is a life-threatening condition characterized by physiologic, pathologic, and biochemical abnormalities induced by infection. 1 The incidence of sepsis is very high, and it remains an important public health issue and a huge burden across all economic regions. 2 Although many parameters are available for the diagnosis and evaluation of sepsis, it is also imperative to develop valuable indicators to predict the prognosis of sepsis. Patients with sepsis have an uncontrolled immune response and protracted in ammation due to overwhelming infection. 3 In ammatory and immune cell counts are inexpensively measured and readily available parameters of in ammatory responses that can be obtained from whole blood count assays. 4 Many studies have indicated that blood cell ratios are valuable biomarkers with which to measure systemic in ammation and predict the prognosis of some health disorders, such as cardiovascular diseases. 5,6 The ratio of the sum of the peripheral neutrophil and monocyte counts to the peripheral lymphocyte count (NMLR) is an indicator of the in ammatory and immune status. Some studies have suggested that the NMLR is a prognostic indicator for in ammatory and immune disorders 7,8 and acute myocardial infarction. 9 However, evidence supporting the correlation between the NMLR at the time of admission to the intensive care unit (ICU) and the 30-day mortality of patients with sepsis remains scarce. Therefore, we conducted the present study to explore the relationship between the ICU admission NMLR and 30-day mortality of patients with sepsis.

Data source
The data used in our study were extracted from the Medical Information Mart for Intensive Care IV (MIMIC-IV version 1.0) database, which contains the hospitalization information of patients admitted to the Higher Medical Center in Boston, MA, USA from 2008 to 2019. We nished the required "Data or Specimens Only Research" course to use the database and obtained the corresponding certi cate (Record ID: 11347834). Informed consent from individual patients was not required because the patients' private information was recoded.
Participants and data extraction Data were extracted from the MIMIC-IV database using Navicat Premium 15, which was installed to run structure query language (SQL), and the code was obtained from the MIMIC Code Repository (https://github.com/MIT-LCP/mimic-code). Patients aged > 18 years who were admitted to the ICU and diagnosed with sepsis were included in this retrospective study. According to the Sepsis-3 de nition, sepsis was con rmed in patients with a Sequential Organ Failure Assessment (SOFA) score of ≥ 2 points accompanied by infection. 10 Patients were excluded from the study when repeated ICU stays were recorded and when NMLR data were missing. The following patient information was extracted: age, sex, race, hematocrit, hemoglobin, platelet count, white blood cell count, anion gap, bicarbonate, blood urea nitrogen, calcium, chloride, creatinine, glucose, sodium, potassium, monocyte count, neutrophil count, lymphocyte count, heart rate, systolic blood pressure, diastolic blood pressure, mean blood pressure, respiratory rate, temperature, peripheral oxygen saturation, renal replacement therapy on rst day, SOFA score, systemic in ammatory response syndrome score, congestive heart failure, diabetes, hypertension, obstructive pulmonary disease, and peripheral vascular disease. The severity scores and all blood sample parameters were collected on the rst day of ICU admission.

Statistical analysis
The data were analyzed using R version 4.2.1. The Kolmogorov-Smirnov test was used to assess the normality of the data distribution. Continuous variables are presented as median [interquartile range] and were compared using the Kruskal-Wallis test, whereas categorical variables are presented as count (percentage) and were compared using the chi-square test or Fisher's exact test. We conducted univariate and multivariate Cox regression analyses to identify the risk factors for 30-day mortality of patients with sepsis. A restricted cubic spline was used to determine the cut-off value and visualize the nonlinear relationship between the ICU admission NMLR and 30-day mortality. Kaplan-Meier analysis was used to compare the survival status of two groups with different ICU admission NMLR levels.
Increased ICU admission NMLR was associated with higher 30-day mortality We used restricted cubic splines with four knots at the 5th, 35th, 65th, and 95th centiles to model the nonlinear relationship between the ICU admission NMLR and 30-day mortality. The model was adjusted for the above 13 cofounders that accorded with the proportional hazards assumption. As shown in Fig. 1, the ICU admission NMLR was nonlinearly associated with 30-day mortality of patients with sepsis (P = 0.0124); the HR increased rapidly when the ICU admission NMLR was > 9.482 and then reached a plateau when the ICU admission NMLR was approximately 40. In general, the HR of 30-day mortality increased as the ICU admission NMLR increased.
Next, we divided the study population into a higher ICU admission NMLR group (NMLR > 9.482) and lower ICU admission NMLR group (NMLR < 9.482) according to the cut-off point. We then performed a Kaplan-Meier analysis between the two groups. As shown in Fig. 2, the survival curve in the higher ICU admission NMLR group was signi cantly lower than that in the lower ICU admission NMLR group (log-rank test, P < 0.0001). Thus, a higher ICU admission NMLR was associated with increased 30-day mortality.

Discussion
In the current study, we discovered that a higher ICU admission NMLR level was associated with an increased risk of mortality in patients with sepsis. The ICU admission NMLR was nonlinearly associated with the HR of 30-day mortality of patients with sepsis, and the HR was equal to 1 when the ICU admission NMLR was about 9.482.
An uncontrolled immune response and the development of in ammatory disorders are very common in patients with sepsis. Monocytes, neutrophils, and other innate immune cells release proin ammatory cytokines that result in dysregulated in ammatory responses, causing systemic damage. 11 In addition to this innate hyperin ammatory response, patients with sepsis also endure persistent immunosuppression, which may be responsible for the high mortality rate after being discharged. Lymphopenia occurs after sepsis, 12 monocytes and macrophages become vulnerable to mounting a proin ammatory response, 13,14 and neutrophil dysfunction increases the release and activation of immunosuppressive myeloid-derived suppressor cells. 12 These cells coordinately mediate immunosuppression by releasing anti-in ammatory cytokines such as interleukin 10 in patients with sepsis. 14 Therefore, the activity of innate immune cells is closely associated with the immune and in ammatory status of patients with sepsis.
The NMLR is an indicator of the in ammatory and immune status, and it demonstrates the balance of neutrophils/monocytes and lymphocytes in the systemic in ammatory response. 15 Thus, the NMLR has been widely studied with respect to its prognostic value for diseases such as hepatocellular carcinoma, cardiovascular diseases, and multiple myeloma. Liao et al. 15 revealed that the NMLR could better predict the postoperative recurrence-free survival and overall survival of patients with hepatocellular carcinoma than could other predictive factors. Yan et al. 8 found that adding the NMLR to the Canada Acute Coronary Syndrome Risk Score model signi cantly improved the model e ciency, and the NMLR could effectively predict the cardiovascular mortality in very old patients with acute myocardial infarction. Pang et al. 7 reported that a lower NMLR (< 1.90) was an independent prognostic factor for progression-free survival as well as early immune reconstruction and a lower disease burden in patients with multiple myeloma who were treated with bortezomib + cyclophosphamide + dexamethasone regimen therapy. However, no study to date has investigated the prognostic value of the NMLR in patients with sepsis. Therefore, this is the rst study to focus on the relationship between the ICU admission NMLR and sepsis-related mortality. Our results con rmed the predictive value of the ICU admission NMLR. The results showed that patients with sepsis in the non-survival group had a higher ICU admission NMLR value than those in the survival The present study had three main limitations. First, the laboratory data used in the study were collected on the rst day of ICU admission; thus, we could not analyze the continuous change in the NMLR. Second, selection bias and confounding bias were unavoidable in this retrospective observational study. Finally, the data in our study were extracted from a single-center MIMIC IV database and therefore may not be representative enough.

Conclusion
As a result, the present study demonstrated that NMLR was a simple and valuable biomarker related to mortality of patients with sepsis. Patients with ICU admission NMLR not less than 9.482 should be treated more carefully as they are more likely to have an adverse prognosis.

Figure 1
Restricted cubic spline curve for the non-linear relation between hazard ratios of 30-day mortality and ICU admission NMLR.

Figure 2
Kaplan-Meier plots for 30-day mortality by ICU admission NMLR strata.

Supplementary Files
This is a list of supplementary les associated with this preprint. Click to download. Rawdata.csv