key: cord-0751399-hzzqyypx
authors: Fois, Alessandro G.; Paliogiannis, Panagiotis; Scano, Valentina; Cau, Stefania; Babudieri, Sergio; Perra, Roberto; Ruzzittu, Giulia; Zinellu, Elisabetta; Pirina, Pietro; Carru, Ciriaco; Arru, Luigi B.; Fancellu, Alessandro; Mondoni, Michele; Mangoni, Arduino A.; Zinellu, Angelo
title: The Systemic Inflammation Index on Admission Predicts In-Hospital Mortality in COVID-19 Patients
date: 2020-12-04
journal: Molecules
DOI: 10.3390/molecules25235725
sha: a40d1377d3ff3d057e4c7b05ab3c8830c61453a3
doc_id: 751399
cord_uid: hzzqyypx

Background. The rapid onset of a systemic pro-inflammatory state followed by acute respiratory distress syndrome is the leading cause of mortality in patients with COVID-19. We performed a retrospective observational study to explore the capacity of different complete blood cell count (CBC)-derived inflammation indexes to predict in-hospital mortality in this group. Methods. The neutrophil to lymphocyte ratio (NLR), derived NLR (dNLR), platelet to lymphocyte ratio (PLR), mean platelet volume to platelet ratio (MPR), neutrophil to lymphocyte × platelet ratio (NLPR), monocyte to lymphocyte ratio (MLR), systemic inflammation response index (SIRI), systemic inflammation index (SII), and the aggregate index of systemic inflammation (AISI) were calculated on hospital admission in 119 patients with laboratory confirmed COVID-19. Results. Non-survivors had significantly higher AISI, dNLR, NLPR, NLR, SII, and SIRI values when compared to survivors. Similarly, Kaplan–Meier survival curves showed significantly lower survival in patients with higher AISI, dNLR, MLR, NLPR, NLR, SII, and SIRI. However, after adjusting for confounders, only the SII remained significantly associated with survival (HR = 1.0001; 95% CI, 1.0000–1.0001, p = 0.029) in multivariate Cox regression analysis. Conclusions. The SII on admission independently predicts in-hospital mortality in COVID-19 patients and may assist with early risk stratification in this group.

In December 2019, an ongoing outbreak of unexplained pneumonia in China gained global attention [1] . Gene sequencing allowed the identification of a novel β-coronavirus as the responsible

A total of 119 COVID-19 patients (77 men and 42 women) were included in the study ( Table 1 ). The median age was 72 (IQR: 60-81) years. Ninety patients (75.6%) were discharged alive, whereas the remaining 29 (24.4%) died. Of the 119 patients, 81 (68.1%) had one or more pre-existing diseases, of which cardiovascular disease, respiratory disease, and diabetes were the most frequent (between 58 and 21%). The median hospitalization duration was 15 (IQR: 10-26) days. As reported in Table 1 , non-survivors were significantly older (80 years, IQR 74-85 years vs. 68 years, IQR 57-78 years; p < 0.001), suffered more frequently from cardiovascular disease (79% vs. 51%, p = 0.008), and had higher values of the Charlson comorbidity index (median: 6.0, IQR 5.0-8.0 vs. 3.5, IQR 2.0-6.0, p < 0.001). Survivors had significantly higher P/F ratio values (278 ± 90 vs. 208 ± 88), longer time interval between disease onset and admission (median: 7.0 days, IQR 4.0-9.0 days vs. 4.0 days, IQR 1.5-6.0 days, p = 0.006), and longer hospital stay (median: 20 days, IQR: 13-34 days vs. 6 days, IQR 4-12 days). A significant difference between survivors and non-survivors was also observed in intensity of care (p = 0.03). In addition, non-survivors had significantly higher values of white blood cells (WBCs) (median: 9.16 × 10 9 L; IQR: 5.65-13.52 × 10 9 L vs. 6.47 × 10 9 L IQR: 5.00-8.66 × 10 9 L, p = 0.006), neutrophils (median: 7.30 × 10 9 L; IQR: 3.75-11.15 × 10 9 L vs. 5.00 × 10 9 L IQR: 3.56-6.30 × 10 9 L, p = 0.012), and lower values of lymphocytes (median: 0.70 × 10 9 L; IQR: 0.60-1.03 × 10 9 L vs. 1.00 × 10 9 L IQR: 0.70-1.20 × 10 9 L, p = 0.012). By contrast, there were no significant differences between survivors and non-survivors in gender, body mass index (BMI), smoking status, chest CT severity score, kidney disease, respiratory disease, diabetes, autoimmunity disease, malignancies, use of angiotensin converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs), monocytes, platelets, red cell distribution width (RDW), and mean platelet volume (MPV). With respect to survival, the optimal cutoff values identified by ROC analysis were as follows: AISI, 798; dNLR, 6. Table 4 showed that only the SII was significantly associated with survival (HR = 1.0001; 95% CI, 1.0000-1.0001, p = 0.029) after correction for age, P/F ratio, intensity of care, and Charlson comorbidity index. A trend towards statistical significance was also observed with the dNLR (HR = 1.0926; 95% CI, 0.9943-1.2006, p = 0.066) and the PLR (HR = 1.0006; 95% CI, 1.0000-1.0013, p = 0.058). Table 5 shows demographic, clinical, and hematological characteristics of COVID-19 patients stratified according to SII values. Patients with SII > 1835 had lower P/F ratios when compared with patients with SII ≤ 1835 (226 ± 79 vs. 301 ± 85, p < 0.0001); higher chest CT severity score (median: 21.0, IQR 13.3-23.0 vs. 9.0, IQR 5.0-14.0, p < 0.001); increased values of WBC (median: 9.90 × 10 9 L; IQR: 7.49-12.60 × 10 9 L vs. 5.90 × 10 9 L IQR: 4.8-7.87 × 10 9 L, p < 0.001), neutrophils (median: 8.65 × 10 9 L; IQR: 6.00-11.60 × 10 9 L vs. 4.40 × 10 9 L IQR: 3.40-5.55 × 10 9 L, p < 0.001), and platelets (267 × 10 9 L; IQR: 220-361 × 10 9 L vs. 183 × 10 9 L IQR: 147-233 × 10 9 L, p < 0.001); and reduced values of lymphocytes (median: 80.64 × 10 9 L; IQR: 0.50-0.80 × 10 9 L vs. 1.00 × 10 9 L IQR: 0.80-1.35 × 10 9 L, p < 0.001). Furthermore, patients with higher SII values had increased mortality rate (42% vs. 16%, p = 0.002). No significant differences were observed in other variables. 

This study described 119 COVID-19 patients hospitalized at four referral centers in Sardinia (Italy) from 15 March to 15 May 2020, with clinical and demographic characteristics similar to those recently described in other COVID-19 cohorts [1, 6, [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] . The lag time between the onset of symptoms and admission to hospital, a crucial factor in the community transmission rate, was 6.5 days (IQR 3-8 days), within the range of previous reports, between 4 and 12 days [17, [19] [20] [21] [22] 24, 25, 28, 30, 31] . The median length of hospital stay in our cohort (15 days, IQR 10-26 days) was also similar to that of recent reports (between 12 and 22 days) [25, 29, 31, 32] . As previously reported, we found that disease severity was significantly related to age [6, 18, 25, [27] [28] [29] 32, 33] , cardiovascular disease [6, 18, 29, 33, 34] , interval between disease onset and admission [29, 32] , and P/F ratio [35] .

Several laboratory abnormalities were reported in COVID-19 patients, particularly in severe and critically ill patients . In line with other studies, among hematological parameters, leukocytosis, lymphopenia, and increased neutrophil count were related to disease severity in our cohort [1, 6, 18, 19, 25, [27] [28] [29] [36] [37] [38] [39] [40] [41] . Neutrophils, the most abundant circulating white blood cells, are an important component of the immune system. They represent the first line of the innate immune defense, since they play a fundamental protective role during infection from bacteria and fungi, by killing these microorganisms by phagocytosis as well as neutrophil extracellular trap (NET) formation. However, their role in viral infections remains unclear. In mice infected by SARS-CoV, neutrophils seem not necessary for virus clearance from pulmonary cells and host survival [42] . Lungs from autopsy of patients affected by COVID-19 showed extensive neutrophil infiltration in pulmonary capillaries with extravasation into the alveolar space. The presence of both acute capillaritis as well as trachea neutrophilic mucositis demonstrates widespread inflammation across the airways [42] .

In addition, inflammatory cell accumulation associated with endothelial cells infection during COVID-19 disease may induce endothelitis in different organs, thus contributing to systemic damage of microcirculatory function and leading to the phenomenon known as "happy hypoxia" [42] . On the other hand, the lymphopenia observed in COVID-19 seems to be linked to the ability of the virus to infect T cells through the angiotensin-converting enzyme 2 (ACE2) receptors and CD147-spike protein [43] . Therefore, a decreased level of CD3+, CD4+, and CD8+ T lymphocytes and an increased number of regulatory T cells are frequently observed in COVID-19 disease.

The increase of proinflammatory cytokines during T cell lymphopenia predisposes severe COVID-19 patients to a cytokine storm, thus resulting in multi-organ failure and death. In general, T lymphocytes CD4+ and CD8+ decrease is associated with disease severity and leads to increased NLR values, which have been reported to be a more sensitive biomarker of inflammation than the individual levels of neutrophils and lymphocytes [43] . In agreement with previous reports, we found increased values of NLR and dNLR in severe COVID-19 disease patients [18, 19] . However, we also report for the first time that other blood cell count-derived inflammation indexes such as NLPR, SII, SIRI, and AISI are also significantly associated with disease severity. In particular, in our study, the AUC values of both NLR and NLPR were the highest, among the combined indexes evaluated, in predicting disease severity (about 0.70). The data of NLR AUC agreed well with those of previous reports, ranging between 0.65 and 0.73 [44] [45] [46] . In addition, we found that the AUC was significant with the dNLR, AISI, and SIRI, and had borderline significant with the SII and MLR (p = 0.060 and p = 0.054, respectively).

Kaplan-Meier survival curves using cut-off values obtained from ROC curves showed that survival was significantly associated with AISI, dNLR, MLR, NLPR, NLR, SII, and SIRI ( Figure 1 ). However, after correction for age, P/F ratio, intensity of care, and Charlson comorbidity index, confounders identified in univariate analysis, only the SII remained associated with survival after multivariate Cox regression analysis. The SII includes three peripheral blood parameters, namely neutrophil, platelet, and lymphocyte count, which comprehensively summarizes the balance of host immune and inflammatory status. It has been already suggested as a prognostic biomarker in sepsis patients [47] . In addition, the SII has also been shown to be associated with worse survival in small cell lung cancer, hepatocellular carcinoma, colorectal cancer, and gastric cancer [48] [49] [50] [51] . Recently, it has also been reported that the SII was significantly altered in COVID-19 patients when compared to healthy controls, suggesting a diagnostic role in SARS-CoV2-infected patients [10] . In addition, in multivariate Cox regression analysis, we found a borderline significance between worse survival and PLR (p = 0.058) and dNLR (p = 0.066). The data on PLR agree with previous findings by Qu R. et al. that reported that the PLR may predict mortality in COVID-19 patients [52] . Interestingly, patients with higher SII values had a significantly worst P/F ratio and chest CT severity score, with no differences regarding the Charlson comorbidity index; this suggests that SII might reflect specifically the pulmonary and respiratory damage occurring in COVID-19 patients rather than a general impairment of their clinical conditions due to comorbidities.

Some limitations of this study should be underlined, including its retrospective nature and the relatively small sample size, which may have impacted the statistical analysis, even if patients were recruited from four different centers, thus improving the generalization of the results. On the other hand, this is the first study to investigate and compare the prognostic roles of a wide range of blood cell count systemic inflammation indexes in COVID-19.

We retrospectively studied 119 COVID-19 patients admitted to the Respiratory Disease and Infectious Disease Units of the University Hospital of Sassari, the Pneumology Unit of the Santissima Trinità Hospital of Cagliari, and the Pneumology Unit of the Mater Olbia Hospital of Olbia, Sardinia, Italy, between 15 March and 15 May 2020. COVID-19 disease was confirmed by reverse transcription polymerase chain reaction (RT-PCR) in all cases. Demographic, clinical, and laboratory data were entered in a dedicated electronic database. In particular, we assessed the following blood cell count inflammation parameters: white blood cell count (WBC), monocytes, lymphocytes, neutrophils, platelets, red blood cell distribution width (RDW), and mean platelet volume (MPV). We then extrapolated combined blood cell indexes of systemic inflammation: the NLR (neutrophil/lymphocyte ratio), dNLR (neutrophils/(white blood cells − neutrophils)), PLR (platelet/lymphocyte ratio), MPR (mean platelet volume/platelet ratio), NLPR (neutrophil/(lymphocyte × platelet ratio)), MLR (monocyte/lymphocyte ratio), SIRI ((neutrophils × monocytes)/lymphocytes), SII ((neutrophils × platelets)/lymphocytes) and AISI ((neutrophils × monocytes × platelets)/lymphocytes). We also collected information regarding the intensity of care received during hospitalization in terms of respiratory support (oxygen supplementation, non-invasive or invasive respiratory support), established parameters of comorbidity (Charlson comorbidity index), hypoxia (PaO 2 /FiO 2 ), and lung inflammation severity (chest CT severity score).

The patients were monitored until in-hospital death (non-survivors) or discharge (survivors). The criteria for discharge were (i) fever absence for at least 3 days; (ii) signs of improvement on chest CT scan or X-ray; (iii) two consecutive negative nucleic acid tests performed at least 24 h from each other. The study was conducted in accordance with the declaration of Helsinki and was approved by the ethics committee of the University Hospital (AOU) of Cagliari (PG/2020/10915).

Data are expressed as mean values (mean ± SD) or median values (median and IQR). The Kolmogorov-Smirnov test was performed to evaluate variable distribution. Between-group differences of continuous variables were compared using unpaired Student's t-test or Mann-Whitney rank sum test, as appropriate. Differences between categorical variables were evaluated by Fisher test or chi-squared test, as appropriate. Receiver operating characteristics (ROC) curve analysis was performed to estimate optimal cut-off values, maximizing sensitivity and specificity according to the Youden index. For survival analysis, time zero was defined as the time of hospital admission.

Survival probability for CBC-derived inflammation indexes was estimated using the means of the Kaplan-Meier curves with the end point being death. Cox proportional hazards regression was performed for both univariate and multivariate analyses. To avoid collinearity bias, the independent prognostic power of the combined blood cell count-derived indexes was separately assessed for each parameter, by correcting for confounders that have a p < 0.2 in univariate analysis (age, P/F ratio, intensity of care, and Charlson comorbidity index). Statistical analyses were performed using MedCalc for Windows, version 19.4.1 64 bit (MedCalc Software, Ostend, Belgium).

The results of this retrospective study showed that the SII is the most significant prognostic biomarker for survival in patients with SARS-CoV2-infected patients when compared to other widely employed blood cell count-derived inflammation indexes such as the NLR, dNLR, PLR, MLR, NLPR, MPR, AISI, and SIRI. Properly designed prospective studies should be performed to confirm the prognostic ability of SII in COVID-19 patients and its utility in the early identification of high-risk patients and the implementation of optimal individualized treatment strategies. 

The authors declare no conflict of interest.

Clinical features of patients infected with 2019 novel coronavirus in

Higher level of neutrophil-to-lymphocyte is associated with severe COVID-19

Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: Summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention

Coronavirus disease 2019: What we know?

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: A retrospective cohort study

Clinical characteristics of hospitalized patients with SARS-CoV-2 infection: A single arm meta-analysis

Clinical, laboratory and imaging features of COVID-19: A systematic review and meta-analysis

Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: A single-centered, retrospective, observational study

Role of hematological parameters in COVID-19 patients in the emergency room

Blood Cell Count Derived Inflammation Indexes in Patients with Idiopathic Pulmonary Fibrosis

Blood cell count indexes as predictors of outcomes in advanced non-small-cell lung cancer patients treated with Nivolumab

Associations between the neutrophil-to-lymphocyte and the platelet-to-lymphocyte ratios and the presence and severity of psoriasis: A systematic review and meta-analysis

The neutrophil-to-lymphocyte ratio as a marker of chronic obstructive pulmonary disease and its exacerbations: A systematic review and meta-analysis

Neutrophil to lymphocyte ratio as a predictor of thyroid papillary carcinoma

Diagnostic value of peripheral hematologic markers for coronavirus disease 2019 (COVID-19): A multicenter, cross-sectional study

The diagnostic and predictive role of NLR, d-NLR and PLR in COVID-19 patients

Risk factors for death in 1859 subjects with COVID-19

Laboratory test alterations in patients with COVID-19 and non COVID-19 interstitial pneumonia: A preliminary report

Liver injury in patients with severe acute respiratory syndrome coronavirus-2 infection: A systematic review and meta-analysis

Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: A descriptive study

Clinical Characteristics of 138 Hospitalized Patients with 2019 Novel Coronavirus-Infected Pneumonia in

Genomic characterisation and epidemiology of 2019 novel coronavirus: Implications for virus origins and receptor binding

Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus-Infected Pneumonia

Clinical Characteristics of Coronavirus Disease 2019 in China

Risk factors associated with disease severity and length of hospital stay in COVID-19 patients

A Tool for Early Prediction of Severe Coronavirus Disease 2019 (COVID-19): A Multicenter Study Using the Risk Nomogram in Wuhan and Guangdong

Clinical Characterization of 162 COVID-19 patients in Israel: Preliminary Report from a Large Tertiary Center

Risk factors for severity and mortality in adult COVID-19 inpatients in Wuhan

Epidemiological features and medical care-seeking process of patients with COVID-19 in Wuhan

Evaluation of antiviral therapies for coronavirus disease 2019 pneumonia in Shanghai

The timeline and risk factors of clinical progression of COVID-19 in Shenzhen

Predictors of progression from moderate to severe coronavirus disease 2019: A retrospective cohort

The characteristics and outcomes of 681 severe cases with COVID-19 in China

Clinical characteristics of coronavirus disease (COVID-19) early findings from a teaching hospital in Pavia

Derivation and Validation of a Predictive Score for Disease Worsening in Patients with COVID-19

Clinical characteristics and day-90 outcomes of 4244 critically ill adults with COVID-19: A prospective cohort study

Hematological findings and complications of COVID-19

Organ-specific manifestations of COVID-19 infection

Comparison of clinical, para-clinical and laboratory findings in survived and deceased patients with COVID-19: Diagnostic role of inflammatory indications in determining the severity of illness

Predicting Disease Severity and Outcome in COVID-19 Patients: A Review of Multiple Biomarkers

Neutrophils and Neutrophil Extracellular Traps Drive Necroinflammation in COVID-19

Use of Neutrophil-to-Lymphocyte and Platelet-to-Lymphocyte Ratios in COVID-19

Neutrophil-to-Lymphocyte Ratio and Outcomes in Louisiana COVID-19 Patients

Clinical and hematological characteristics of 88 patients with COVID-19

The value of clinical parameters in predicting the severity of COVID-19

Systemic immune inflammatory index in sepsis

Systemic Immune-inflammation Index, Based on Platelet Counts and Neutrophil-Lymphocyte Ratio, Is Useful for Predicting Prognosis in Small Cell Lung Cancer

Systemic Immune-Inflammation Index Predicts Prognosis of Patients after Curative Resection for Hepatocellular Carcinoma

Prognostic and clinicopathological significance of systemic immune-inflammation index in colorectal cancer: A meta-analysis

Comparison of the prognostic value of immunoinflammation-based biomarkers in patients with gastric cancer

Platelet-to-lymphocyte ratio is associated with prognosis in patients with coronavirus disease-19

Sample Availability: Data are available from the corresponding author upon reasonable request.Publisher's Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.