key: cord-0683753-9ak3j97f
authors: Kaya, Hiroyasu; Kaji, Masahide; Usuda, Daisuke
title: Soluble interleukin-2 receptor levels on admission associated with mortality in coronavirus disease 2019
date: 2021-03-09
journal: Int J Infect Dis
DOI: 10.1016/j.ijid.2021.03.011
sha: 78bb9ed5a50922eacff49346582e6f8a8a32e81f
doc_id: 683753
cord_uid: 9ak3j97f

OBJECTIVES: Early and simple detection of high-risk groups is crucial to minimizing severe coronavirus disease 2019 (COVID-19)-related death, and soluble interleukin 2 receptor (sIL2R) has been suspected to offer a prognostic marker for infectious diseases. We validated the usefulness of sIL2R as a marker for the related deaths. METHODS: This retrospective observational study enrolled participants who showed positive results for severe acute respiratory syndrome coronavirus 2 RNA admitted to our hospital between April 1 and September 30, 2020. Of the 102 patients enrolled in this study, sIL2R levels were measured in 87 patients. For comparisons between survival and non-survival groups, potential confounding variables were entered into univariate models, and variables showing significant correlations (p < 0.05) in those models were added to a multivariate model. RESULTS: Age ≥60 years and sIL2R level ≥1060 U/ml were significantly associated with mortality in univariate analyses. Only sIL2R level correlated significantly with mortality on multivariate logistic regression analysis. Further, sequential sIL2R levels in 3 patients were increased at progression or death. CONCLUSION: SIL2R on admission and sequential monitoring of sIL2R might reflect disease severity.

In December 2019, an outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections developed in Wuhan, China, and subsequently spread throughout the world. Several risk factors or predictors of disease severity have been reported and severe coronavirus disease 2019 has been correlated with various immunological abnormalities, cytokine release and the coagulation cascade. An important step toward avoiding increasing numbers of COVID-19-related deaths is early, simple detection of high-risk groups.

We performed a retrospective observational study at Toyama Prefectural Central Hospital in Japan. In this study, all patients who tested positive for SARS-CoV-2 RNA and were admitted to our hospital between April 1 and September 30, 2020 were enrolled. The primary outcome measure was infectious death. To estimate potential clinical relevance, we collected baseline, clinical, laboratory data and outcomes as parameters: age, sex, and measured values of soluble interleukin 2 receptor (sIL2R), CD4/25 double positive cell, procalcitonin (PCT) and thrombin-anti-thrombin complex (TAT). Previous reports have suggested sIL2R as a marker for activated lymphocytes (Murakami J. 2019) . Immunologic criteria for provisional diagnosis of hemophagocytic lymphohistiocytosis include elevated levels of sIL2R (Filipovich A. 2009 ). The test of sIL2R also is more easily and faster than other cytokines. We prompted to test for level J o u r n a l P r e -p r o o f of sIL2R. In univariate analyses, the  2 or Fisher's exact test was used for categorical variables. Cox-regression analysis was applied to identify predictors of death in multivariate analysis. Cut-off values were determined by receiver operating characteristic (ROC) curve analysis and patients were allocated into two groups on the basis of these cut-off values. In addition, we analyzed relationships between groups determined using those cut-offs for each factor and outcomes. EZR version 1.54 was used for all statistical analyses (Kanda Y.2013) .

A total of 102 patients were enrolled in this study. Of these, 42 patients had data available for the CD4/25 double-positive cell count. Levels of sIL2R were measured in 87 patients, PCT levels in 93 patients, and TAT levels in 40 patients. Only 4 patients underwent sequential measurement of sIL2R levels, at diagnosis, progression and recovery or death. First, cut-off values were determined by ROC curve analysis. Cut-off values for CD4/25 cell count, sIL2R, PCT and TAT to predict outcomes were 90 /μl, 1060 U/ml, 0.15 ng/ml, and 4 ng/ml, respectively. Table 1 shows mortality rates for groups by risk factor. Age  60 years and sIL2R level  1060 U/ml correlated significantly with mortality in univariate analyses. Only sIL2R level  1060 U/ml was significantly associated with mortality on multivariate logistic regression analysis based on the results of univariate analyses (Table 1) . Multivariate analysis identified sIL2R as J o u r n a l P r e -p r o o f a significant independent risk factor. Two of sIL2R level 1060U/ml seven patients had no pneumonia, two patients had pneumonia but no treatment of oxygen and other three patients were severe condition but recovered. One patient of two deaths where ≤1060U/ml is case 1 of Figure 1 . Sequential sIL2R levels in Cases 1, 3 and 4 were increased at progression or death.

On the other hand, sIL2R level in Case 2 was decreased at recovery (Figure 1 ). The interval from diagnosis to progression was 2-4 weeks and that from progression to recovery or death was 2 weeks.

Zhou et al. reported older age and D-dimer level as potential risk factors that could help clinicians identify COVID-19 patients with poor prognosis at an early stage (Zhou F.2020) . Other studies identified PCT as a potential predictor of disease severity (Henry M.2020 , Lippi G.2020 , Lippi G.2020 ). Severe COVID-19 patients show various immunological abnormalities, including reduced T-cell counts and cytokine release syndrome. Immune system hyperactivation and paralysis reportedly drive immunopathology in severe COVID-19 (Kalfaoglu B. 2020) . Sugiyama et al. reported that serum CCL17 level offers a predictive marker for distinguishing between mild/moderate and severe/critical disease in patients with COVID-19 (Sugiyama M.2020) . From our data, only sIL2R levels  1060 U/ml correlated significantly with J o u r n a l P r e -p r o o f mortality in multivariate logistic regression analysis based on the results of univariate analyses. We thus considered that sIL2R offered a good reflection of COVID-19 severity. PCT may not have reflected the pathology of COVID-19 because of the complication of bacterial infection in the form of aspiration pneumonia among elderly patients. We considered that the number of patients examined for TAT was too small to identify any significant correlation with outcome. Fewer CD4/25 double-positive cells tended to be associated with high mortality, contradicting the results for sIL2R, but we considered that the number of patients examined for CD4/25 was again probably too small to show a significant correlation with outcome.

In summary, we identified sIL2R as a predictive marker of cytokine release syndrome and immune overreaction against COVID-19. Since even patients with low sIL2R levels at diagnosis may progress to severe disease, and sIL2R might offer a predictor of disease severity, sequential monitoring of sIL2R may be warranted.

This research did not receive any specific grants from funding agencies in the public, commercial, or not-for-profit sectors.

Due to the observational and retrospective nature of the study, specific informed consent from individual patients was not required. All data were generated from routine standard clinical management of the patients.

All authors have no conflict of interest to declare. 

Hemophagocytic lymphohistiocytosis (HLH) and related disorders

Hematologic, biochemical and immune biomarker abnormalities associated with severe illness and mortality in coronavirus disease 2019 (COVID-19): a meta-analysis

Investigation of the freely available easy-to-use software 'EZR' for medical statistics

T-Cell Hyperactivation and Paralysis in Severe COVID-19 Infection Revealed by Single-Cell Analysis Front

Procalcitonin in patients with severe coronavirus disease

COVID-19): a meta-analysis

Thrombocytopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: a meta-analysis

Serum Soluble interleukin-2 Receptor Levels for Screening for Malignant Lymphomas and Differential Diagnosis From Other Conditions

Serum CCL17 level becomes a predictive marker to distinguish between mild/moderate and severe/critical disease in patients with COVID-19 gene

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

We would like thank the medical staff at the Toyama Prefectural Central Hospital. In