Simplified immune-dysregulation index: a novel marker predicts 28-day mortality of intensive care patients with COVID-19.

Dear Editor,

Since December 2019, a coronavirus disease-2019 (COVID-19) was first reported in Wuhan, China, which was caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and expeditiously spread to countries worldwide with massive mortality [1]. The response of lymphocytes in COVID-19 is characterized by a phenomenon of lymphopenia and hypercytokinemia, and is correlated with disease severity and prognosis [2]. Besides, interleukin-6 (IL-6) may be the key cytokine leading to inflammatory storm in COVID-19 [3]. Hence, we develop a simplified immune-dysregulation index—the level of IL-6 to lymphocytes count ratio—to define the immune-dysregulation in COVID-19. We aimed to evaluate the predictive value of IL-6/lymphocyte in patients with COVID-19.

We conducted a retrospective study based on patients with confirmed diagnosis of COVID-19 admitted to the intensive care units in Tongji Hospital. The inclusion and exclusion criteria were presented in the online supplement. IL-6 (pg/ml) and lymphocytes count (106/ml) within the first day after hospital admission were collected. IL-6/lymphocyte was calculated. We used the highest ratio if a variable was recorded more than once. The primary outcome was 28-day mortality. Multivariate regression was selected to characterize the association between IL-6, lymphocyte, IL-6/lymphocyte and 28-day mortality, respectively (description in the online supplement), we then model the nonlinear relationship between IL-6/lymphocyte and 28-day mortality using splines, and the predictive value of IL-6/lymphocyte, IL-6 and lymphocytes for 28-day mortality was compared according to receiver operating characteristic (ROC) curves, net reclassification improvement (NRI) and integrated discrimination improvement (IDI). We also attempt to stratified patients through the IL-6/lymphocyte. The study was approved by Tongji Hospital Ethics Committee.

A total of 172 patients were included in our study (description in the online supplement). Overall 28- day mortality was 50.5%. Baseline characteristics between survivors and non-survivors are presented in eTable 1. Survivors had a higher lymphocytes count (0.94 (0.73–1.28) vs. 0.53 (0.38–0.74); p < 0.001) and a lower IL-6 (7.1 (2–21.6) vs. 61.1 (33.4–137.4); p < 0.001) compared non-survivors. Statistical analysis demonstrated that lymphocyte is negatively correlated with IL-6 (R = − 0.26; p < 0.001) (eFig. 1). IL-6/lymphocyte was significantly higher in non-survivors than that in survivors (125.5 (56.9–267.4) vs. 8.3 (2.1–23.4); p < 0.001). The logistic regression analyses showed a significantly association between lymphocyte (OR 0.03; 95% CI 0.01–0.17; p < 0.001), IL-6 (OR 1.03; 95% CI 1.01–1.05; p < 0.001); IL-6/lymphocyte (OR 1.05; 95% CI 1.03–1.08; p < 0.001) and 28-day mortality, respectively (eTables 2, 3 and 4). The nonlinear relationship between IL-6/lymphocyte and 28-day mortality is shown in Fig. 1a.

Fig. 1

a Relationship between IL-6/lymphocyte and 28-day mortality for intensive care patients with COVID-19 using splines. Overlying red is fitted linear splines with 95% CI. b ROC curve analysis and comparison of the AUCs for IL-6/lymphocyte, IL-6 and lymphocytes in COVID-19. c Stratified mortality of groups based on the cutoff value of IL-6/lymphocyte in COVID-19. Bars show the percent of patients who died and 95% CI. COVID-19: coronavirus disease-2019; ROC: receiver operating characteristic; AUC: area under the curve

Figure 1b indicates that IL-6/lymphocyte had a higher area under the curve (AUC) (0.93 (95% CI 0.9–0.96)) than IL-6 (0.88 (95% CI 0.83–0.92); p < 0.001) and lymphocytes (0.81 (95% CI 0.75–0.87); p < 0.001). Compared with IL-6, IL-6/lymphocyte resulted in an additive NRI of 22.2% (95% CI: 9.7–34.7%; p < 0.001), and an IDI of 11.8% (95% CI: 8–15.6%; p < 0.001); compared with lymphocyte, IL-6/lymphocyte resulted in an additive NRI of 36.5% (95% CI 17.2–55.8%; p < 0.001) and an IDI of 20.2% (95% CI 11.8–28.6%; p < 0.001). According to the value of IL-6/lymphocyte, we divided patient into three groups: Group I (< 15); Group II (15–50); Group III (> 50), and the Group III had the highest 28-day mortality (Fig. 1c).

The degree of lymphopenia and the increase in inflammatory cytokine—especially IL-6—were associated with poor outcome in patients with COVID-19 [4]. Our study developed a novel marker to represent immune-dysregulation and concluded that IL-6/lymphocyte had an improved predictive value compared to IL-6 and lymphocytes alone. Additionally, IL-6/lymphocyte showed a potential value to identify high-risk patients who needed more timely therapy at the early phase of COVID-19. The limitations of study are the incomplete assessment of immune-dysregulation and a single-center experience. Further researches are needed to compare IL-6/lymphocyte and other immunological indicators, as well as the dynamic change of IL-6/lymphocyte.

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 46 kb)