Soluble IL-2R Levels Predict in-Hospital Mortality in COVID-19 Patients with Respiratory Failure

doi:10.21203/rs.3.rs-709180/v1

Acute respiratory distress syndrome is the primary cause of death in patients with coronavirus disease 2019 (COVID-19) pneumonia. Our study aims to determine the association between serum markers and mortality in COVID-19 patients with respiratory failure. This retrospective study was conducted in a tertiary care hospital in South Korea. Forty-three patients with COVID-19, who required high flow nasal cannulation or mechanical ventilation from Feb 2020-Jan 2021, were included. Demographic and laboratory data were analyzed at baseline and on Day 7 of admission. Older age was associated with mortality. Serum creatinine, troponin, procalcitonin, and soluble interleukin-2 receptor (sIL-2R) at baseline were more elevated in the non-survivor group; however, were not associated with mechanical ventilator use on Day 7 PaO₂/FiO₂ratio, lymphocyte and platelet counts, lactate dehydrogenase, IL-6, c-reactive protein, and sIL-2R on Day 7 were significantly associated with mortality. Delta sIL-2R (Day 7-Day 0) per standard deviation was significantly higher in the non-survivor group (adjusted hazard ratio 3.225, 95% CI 1.151-9.037, p=0.026). sIL-2R could predict mortality in COVID-19 patients with respiratory failure, not mechanical ventilator use. Its sustained elevation suggests a hyper-inflammatory state, and mirrors the severity of COVID-19 in patients with respiratory failure; therefore, warrants further attention.

Immunology

Infectious Diseases

COVID-19

IL-6

Demographic and laboratory

pneumonia

hyper-inflammatory state

In December 2019, an outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection occurred in Wuhan, China. The major cause of death in patients with COVID-19 pneumonia was determined to be multi-organ failure, including respiratory failure—a severe disease often requiring invasive ventilation[1, 2]. For COVID-19 acute respiratory distress syndrome (ARDS), mortality can range between 26% and 61.5% if the patient is admitted to a critical care setting at anytime, and between 65.7–94% in patients who receive mechanical ventilation [2].

Recent studies have discovered risk factors associated with poor prognosis in patients with COVID-19, namely, older age[3], D-dimer[3], and procalcitonin[4]. Among the various inflammatory cytokine and chemokine levels assessed in several studies, tumor necrosis factor alpha (TNF-α), interferon-γ-induced protein 10 (IP-10), monocyte chemoattractant protein 1 (MCP-1), chemokine (C-C motif), ligand 3 (CCL-3), and distinct interleukins (IL) (IL-2, IL-6, IL-7, IL-10) were significantly associated with disease severity, and in particular, elevated among patients admitted to intensive care units (ICUs)[5]. Notably, the serum levels of some interleukins have the potential to discriminate between mild and severe disease, and can possibly be used as prognostic markers[5].

The circulating soluble IL2 receptor (sIL-2R) has been shown to regulate T-lymphocyte activation in various immunological disorders, and increased sIL-2R concentration in plasma predicts a decreased cellular response to IL-2[6].

The host immune response of COVID-19 suggests an immune signature consisting of elevated serum cytokines (IL-6 and TNF-α); elevated inflammatory serum markers including ferritin, lactate dehydrogenase (LDH), D-dimer, C-reactive protein (CRP), and coagulation factors; impaired interferon responses; and peripheral lymphopenia[3, 7, 8].

In this study, among the several inflammatory markers tested in clinical practice, sIL-2R and IL-6 were investigated for an association with mortality in COVID-19 patients with severe respiratory failure.

Forty-nine patients with respiratory failure, aged ≥ 18 years, who required an HFNC or mechanical ventilator during the study period, were included in this study (Fig. 1).

Table 1 shows the baseline characteristics of patients at the time of ICU admission. The median age of patients was 71.0 years and proportion of males was 59.2%. There was no significant difference in the age, sex, presence of hypertension, IL-6, and PaO₂/FiO₂ ratio at the time of ICU admission between the survivor and non-survivor groups. However, the proportion of diabetes mellitus was significantly higher in the non-survivor group than in the survivor group (60% vs. 25.6%, p = 0.041). Furthermore, sIL-2R, creatinine, troponin, and procalcitonin were significantly higher in the non-survivor group than in the survivor group. The median sIL-2R was 1159.0 U/mL (IQR 1099.5-1376.5) in the non-survivor group and 853.0 U/mL (IQR 727.5-1150.5) in the survivor group (p = 0.010).

Table 1 Baseline characteristics of patients on the 1st day of admission

Variable	Survivors (n = 39)	Non-survivors (n = 10)	Total (n = 49)	p-value
Age (years)	70.0 (64.0, 74.0)	78.0 (65.0, 84.8)	71.0(64.5, 77.0)	0.063
Sex, male (%)	22 (56.4)	7 (70.0)	29 (59.2)	0.517
BMI, kg/m²	24.0 (21.4, 25.7)	20.4 (18.8, 25.1)	24.0 (20.5, 25.5)	0.132
Hypertension	22 (56.4)	8 (80.0)	30 (61.2)	0.176
Diabetes	10 (25.6)	6 (60.0)	16 (32.7)	0.041
PaO2/FiO2, kPa	149.8(100.9, 184.3)	125.1 (86.3, 229.2)	148.7 (96.9, 197.9)	0.951
ARDS
Mild	9 (23.1)	3 (30.0)	12 (24.5)
Moderate	21 (53.8)	4 (40.0)	25 (51.0)
Severe	9 (23.1)	3 (30.0)	12 (24.5)
WBC (10³/uL)	8.6 (6.7, 12.6)	6.2 (4.5, 8.5)	8.1(6.0, 11.0)	0.080
Lymphocyte (10³/uL)	0.8 (0.5, 1.0)	0.6 (0.4, 1.0)	0.7 (0.5, 1.0)	0.517
Platelet (10³/uL)	185.0 (136.0, 246.0)	127.5(109.5, 170.8)	181.0(126.0, 232.0)	0.022
Albumin (g/dL)	3.7 (3.3, 3.9)	3.6 (3.1, 3.8)	3.6 (3.3, 3.9)	0.358
Total bilirubin (mg/dL)	0.7 (0.5, 0.9)	0.7 (0.5, 1.3)	0.7(0.5, 1.0)	0.566
Bicarbonate (mmol/L)	23.0 (21.0, 25.0)	22.0 (19.0, 23.5)	23.0 (21.0, 24.8)	0.164
Creatinine (mg/dL)	0.7 (0.6, 1.1)	1.0 (0.9, 2.3)	0.9 (0.6, 1.1)	0.012
Troponin (pg/mL)	12.0 (7.0, 17.3)	33.0 (17.5, 75.8)	12.0 (8.0, 25.3)	0.001
LDH (IU/L)	527.0 (427.0, 639.0)	494.0 (379.8, 652.3)	514.0(420.0, 641.5)	0.779
Procalcitonin (ng/mL)	0.3 (0.1, 0.5)	0.5 (0.4, 1.2)	0.3 (0.1, 0.5)	0.009
Fibrinogen (mg/dL)	471.0(390.8, 613.5)	433.0(305.5, 521.5)	458.0(381.0, 599.0)	0.213
D-dimer (ng/mL)	480.0(273.0, 1386.0)	599.5(328.5, 3858.5)	494.0(294.0, 1288.5)	0.333
Ferritin (ng/mL)	787.8(443.6, 1485.7)	1056.0(422.1, 1688.0)	801.3(446.1, 1485.6)	0.505
CRP (mg/L)	107.6 (59.7, 155.9)	140.3 (55.7, 218.4)	112.2(59.7, 180.3)	0.371
IL-6 (pg/mL)	65.1(17.8, 147.1)	160.1(81.4, 320.7)	89.3(19.4, 158.4)	0.072
Soluble IL2 receptor (U/mL)	853.0(727.5, 1150.5)	1159.0(1099.5, 1376.5)	905.5(740.3, 1230.8)	0.010
Invasive ventilation	11(28.2)	4 (40.0)	14(32.6)	0.582
SOFA score	3.0 (0.3, 8.3)	3.0 (2.8, 4.0)	3.0 (3.0, 3.0)	0.385
APACHE II score	24.0 (20.0, 26.0)	24.5 (19.0, 28.5)	24.0 (20.0, 26.5)	0.391
Hospital day	18.5 (15.0, 24.3)	21.5 (13.5, 33.0)	19.0(15.0, 25.3)	0.695
Abbreviations: BMI, body mass index; ARDS, acute respiratory distress syndrome; WBC, white blood cell; LDH, lactate dehydrogenase; CRP, C-reactive protein; IL-6, interleukin-6; IL-2, interleukin-2; SOFA, Sequential Organ Failure Assessment score; APACHE II, Acute Physiology And Chronic Health Evaluation II.

On the 7th day of hospitalization (Table 2), there were statistically significantly differences in the lymphocyte counts, platelet counts, creatinine, LDH, procalcitonin, CRP, IL-6, and sIL-2R between the two groups. Notably, in the non-survivor group, the sIL-2R on Day 7 was 1313.0 (IQR 1001.3-1963.5), which was higher than that on Day 0, which was 1159.0 (IQR 1099.5-1376.5); however, in the survivor group, sIL-2R levels were decreased on Day 7 (845.0, IQR 563.8-1061.3) compared to that on Day 0 (853.0, IQR 727.5-1150.5). IL-6 concentrations decreased during the course of hospitalization in both groups (survivor group: 17.6 pg/mL, IQR 6.1–51.9; non-survivor group: 100.7 pg/mL, IQR 41.1-244.6).

Table 2 Characteristics of patients on the 7^thday of admission

Variable	Survivors (n=39)	Non-survivors (n=10)	Total (n=49)	p-value
PaO2/FiO2, kPa	216.0(165.4, 290.1)	140.6 (71.3, 160.5)	206.7(141.7, 264.5)	0.001
ARDS
Mild	22 (56.4)	2 (20.0)	24 (49.0)
Moderate	15 (38.5)	5 (50.0)	20 (40.8)
Severe	0 (0.0)	3 (30.0)	3 (6.1)
WBC (10³/uL)	11.7 (7.0, 13.2)	16.2 (7.7, 21.1)	11.8 (7.4, 16.0)	0.189
Lymphocyte (10³/uL)	0.8 (0.5, 1.2)	0.4 (0.2, 0.5)	0.7 (0.4, 1.2)	0.005
Platelet (10³/uL)	272.0 (187.0, 362.0)	117.0 (72.0, 173.8)	242.0 (152.0, 353.0)	0.001
Albumin (g/dL)	2.9 (2.7, 3.2)	2.8 (2.7, 3.0)	2.9 (2.7, 3.2)	0.235
Total bilirubin (mg/dL)	0.6 (0.4, 0.9)	0.7 (0.4, 1.0)	0.6 (0.4, 0.9)	0.795
Bicarbonate (mmol/L)	25.0 (24.0, 29.0)	24.0 (23.0, 28.8)	25.0 (23.0, 29.0)	0.416
Creatinine (mg/dL)	0.6 (0.5, 0.7)	0.9 (0.7, 2.0)	0.6 (0.5, 0.8)	0.001
LDH (IU/L)	402.0(320.5, 475.3)	532.0 (432.5, 637.5)	420.0 (334.0, 532.0)	0.013
Procalcitonin (ng/mL)	0.1 (0.0, 0.1)	0.2 (0.1, 0.7)	0.1 (0.1, 0.2)	0.008
Fibrinogen (mg/dL)	384.5 (348.5, 434.3)	440.5 (256.8, 543.0)	399.0 (349.0, 458.0)	0.634
D-dimer (ng/mL)	982.0 (360.0, 3591.0)	1877.5 (454.8, 6152.0)	987.5 (373.8, 3787.0)	0.338
Ferritin (ng/mL)	548.1 (334.0, 846.5)	592.9 (410.0, 770.5)	571.1 (346.1, 840.1)	0.746
CRP (mg/L)	25.6 (8.7, 52.3)	65.5 (35.5, 112.0)	35.3 (10.1, 54.4)	0.016
IL-6 (pg/mL)	17.9 (6.1, 51.9)	100.7 (41.1, 244.6)	21.6 (8.0, 87.5)	0.001
Soluble IL2 receptor (U/mL)	845.0 (563.8, 1061.3)	1313.0 (1001.3, 1963.5)	949.5 (640.0, 1126.3)	0.001
Invasive ventilation	22 (56.4)	7 (70.0)	27 (59.2)	0.617
Abbreviations: ARDS, acute respiratory distress syndrome; WBC, white blood cell; LDH, lactate dehydrogenase; CRP, C-reactive protein; IL-6, interleukin-6; IL-2, interleukin-2.

Figure 2 shows the scatter plot ofPaO₂/FiO₂ratio,IL-6, and sIL-2R on Days 0 and 7. , there was no significant correlation between IL-6 and PaO₂/FiO₂ratio(p=0.738, Figure 2a), as well as sIL-2Rc and PaO₂/FiO₂ratio (p=0.340, Figure 2b).On Day 7, however, sIL-2Rc was significantly correlated with P/F ratio (p=0.013, Figure 2d); however, IL-6 was not significantly correlated (p=0.167, Figure 2c).

Table 3 shows the baseline characteristics compared between the invasive mechanical ventilation (MV) and non-MV groups. IL-6 and sIL-2R were not associated with MV (p = 0.855 and p = 0.087, respectively).

Table 3 Patients’ demographicsaccording to the application of invasive ventilation

Variable	Non-MV group (n=20)	MV group (n=29)	p-value
Age (years)	71.0 (65.3, 78.6)	70.0 (63.0, 75.5)	0.653
Sex, male (%)	10 (50.0)	19 (65.5)	0.377
BMI, kg/m²	24.2 (20.3, 25.9)	23.8 (20.5, 25.4)	0.717
PaO2/FiO2, kPa	153.2 (127.6, 207.2)	123.1 (87.7, 172.9)	0.186
WBC (10³/uL)	8.2 (7.1, 10.7)	7.7 (5.5, 11.8)	0.307
Lymphocyte (10³/uL)	0.6 (0.5, 1.0)	0.8 (0.5, 0.9)	0.805
Platelet (10³/uL)	182.0 (134.3, 252.0)	164.0(118.0, 208.0)	0.251
Albumin (g/dL)	3.8 (3.5, 4.1)	3.5 (3.2, 3.8)	0.016
Total bilirubin (mg/dL)	0.6 (0.4, 0.7)	0.8 (0.6, 1.2)	0.001
Bicarbonate (mmol/L)	22.0 (20.3, 24.0)	23.0 (21.0, 25.0)	0.382
Creatinine (mg/dL)	0.9 (0.7, 1.1)	0.8 (0.6, 1.0)	0.428
Troponin (pg/mL)	12.0 (9.3, 21.8)	12.5 (7.0, 31.3)	0.963
LDH (IU/L)	507.0(396.3, 569.3)	527.0(428.5, 674.5)	0.211
Procalcitonin (ng/mL)	0.4 (0.1, 0.7)	0.3 (0.1, 0.5)	0.782
Fibrinogen (mg/dL)	488.0 (414.8, 587.0)	445.0(369.0, 615.0)	0.414
D-dimer (ng/mL)	487.0(294.0, 651.5)	527.0(294.0, 4301.5)	0.185
Ferritin (ng/mL)	455.6 (365.0, 985.8)	1098.2(731.0, 1893.4)	0.003
CRP (mg/L)	111.6 (61.7, 144.6)	117.2(59.7, 210.3)	0.490
IL-6 (pg/mL)	100.9 (18.9, 143.8)	65.1 (19.4, 191.5)	0.855
Soluble IL2 receptor (U/mL)	867.0(726.8, 1073.8)	1036.0(754.0, 1364.3)	0.135
Hospital day	15.0 (11.3, 19.0)	22.0 (18.0, 32.0)	<0.001
Mortality	3 (15.0)	7 (24.1)	0.496
Abbreviations: BMI, body mass index; WBC, white blood cell; LDH, lactate dehydrogenase; CRP, C-reactive protein; IL-6, interleukin-6; IL-2, interleukin-2; MV, mechanical ventilation.

Table 4 shows the association between variables including serum markers, and mortality, with Cox regression analysis. The difference in platelet counts between Days 0 and 7 was related to high mortality rates (hazard ratio, HR 0.994, p = 0.019), and the HR per standard deviation (SD) of ΔsIL-2R was 3.145 (p = 0.022) on univariate analysis. The higher the ΔIL-6 per SD, the higher was the mortality rate, though it was not statistically significant (HR 1.664, p = 0.107). Even after correcting several variables using multivariate analysis, ΔsIL-2R was associated with higher mortality, which adjusted the HR to 3.225 (95% confidence interval, CI: 1.151–9.037, p = 0.026).

Table 4 Cox regression analysis of risk factors related to in-hospital mortality in COVID-19 patients with respiratory failure

	Univariable			Adjusted
Variable	HR	95% CI	p-value	HR	95% CI	p-value
Age, years	1.077	0.983-1.180	0.113	1.023	0.942-1.112	0.585
Sex, male	1.622	0.405-6.493	0.495
Initial P/F ratio	0.999	0.993-1.005	0.781	0.997	0.990-1.004	0.340
Δ WBC	1.102	0.970-1.251	0.136
Δ lymphocyte	0.319	0.083-1.227	0.096	0.741	0.096-5.713	0.779
Δ Platelet	0.994	0.990-0.999	0.019	0.993	0.986-1.001	0.069
Δ LDH (IU/L)	1.003	0.999-1.006	0.140
Δ Fibrinogen (mg/dL)	1.001	0.999-1.003	0.385
Δ Ferritin (ng/mL)	0.999	0.997-1.001	0.502
Δ CRP (mg/L)	1.003	0.996-1.011	0.367
Δ IL-6/SD	1.664	0.896-3.088	0.107	1.234	0.594-2.564	0.573
Δ sIL-2R/SD	3.145	1.177-8.406	0.022	3.225	1.151-9.037	0.026
Abbreviations: WBC, white blood cell; LDH, lactate dehydrogenase; CRP, C-reactive protein; IL-6, interleukin-6; sIL-2R, soluble interleukin-2 receptor; SD, standard deviation.

Figure 3 shows the Kaplan-Meier survival curve of IL-6 and sIL-2R. The cut-off value of IL-6 obtained from thereceiver operating characteristiccurve was 191 pg/mL, and it was significantly related to a highermortality rate (p=0.006, Figure 3a). The patient group with sIL-2R above 1083U/mL was significantly associated with mortality (p=0.040, Figure 3b).

In the present study, we evaluated the relationship between immune response-associated laboratory variables and clinical features related to patients with severe COVID-19.Our analysis demonstrated that several immunological parameters are associated with severity and mortality. Among them, we found the clinical significance of IL-6 and sIL-2R inCOVID-19 patients with respiratory failure. IL-6 was not associated with mortalityat admission, but sIL-2R was. Both of these were associated with mortality on the7^th day of admission, and sIL-2R was also correlated with the PaO₂/FiO₂ratio, which reflects the severity of COVID-19 pneumonia. However, sIL-2R was not associated to theuse of mechanical ventilation.

Previous studies have demonstrated the relationship between laboratory markers and clinical outcomes in patients with COVID-19. IL-6, for instance, has been analyzed as a prognostic marker[9-11]. Thrombocytopenia is also known as a factor associated withthe risk of severe disease and mortality in patients with COVID-19, and thus serves as a clinical indicator of worsening illness during hospitalization[12, 13]. Recent studies have suggested an association ofsIL-2R and disease severity[7, 14]. Our study confirms this finding and shows that the level of sIL-2Risassociated with survival as well as disease severity, indicated by thePaO₂/FiO₂ratioin patients withCOVID-19.However, it did not show any association with mechanical ventilator use.

Much of the mortality has been associated with a cytokine storm syndrome in patients admitted to the hospital with COVID-19 pneumonia[15].Defining the COVID-19 cytokine storm syndrome has been challenging, but early reports propose combinations of clinical (eg, fever) and laboratory (e.g., hyperferritinemia) features in determining patients most likely to benefit from treatments for the cytokine storm syndrome[16, 17]. These indicatorsmirrorthe level of systemic hyper-inflammation, lung inflammation, and the severity of organ damage[18]. One of the first strategies toward treating the COVID-19 cytokine storm syndrome was targeting IL-6[19].A recombinant humanized anti-IL-6 receptor monoclonal antibody (Tocilizumab) is being used for treating COVID-19 patients that inhibits the binding of IL-6 to both membrane and soluble IL-6 receptors, blocking IL-6 signaling and reducing inflammation[20]. A recent randomized controlled study demonstrated the efficacy of tocilizumab in improving survival and clinical outcomes[20]. Our study did not show asignificant relationship between the initial level of IL-6 and survival outcome in COVID-19 patients. This may have been due to the small sample size; however, the level of IL-6 on the7^th day of admission was associated with mortality. It is suggested that if the level of IL-6 is consistently high, clinical outcomes couldbe worse; therefore, close observation is needed from the time of initial diagnosis of COVID-19.

Another notable marker among the many inflammatory markers is sIL-2R.Circulating sIL-2R is actively involved in the regulation of T-cell immune responses and is therefore suggested to have a role in disease expression[21]. It has been shown to regulate T-lymphocyte activation in various immunological disorders, and increased sIL-2R concentration in plasma predicts a decreased cellular response to IL-2[22]. Serum levels of sIL-2R are significantly higher in patients with Kawasaki disease[23], who suffer from a systemic inflammatory disease closely associated with infections[24] and autoimmune diseases[25]. A recent study demonstrated that the concentration of sIL-2R in the blood may be a co-indicator of the severity ofCOVID-19 with lymphopenia, through IL-2 signaling inhibition[26, 27]. The cut-off value of sIL-2R related to mortality was 1083U/mL in our study, which was similar to that reported by another recent study,i.e., 1060U/mL [28]. Taken together, our study further supports the presence of elevated serum sIL-2R in COVID-19 patients with respiratory failure and its correlation with poor prognosis.

We recognize that this study did have several limitations: in particular, the small sample size and the use of retrospective data. However, all registered patients were treated with the same protocol, and data on inflammatory markers such as IL-6 and sIL-2R were uniformly collected.Second, since the subjects of this cohort study werethosewith respiratory failure, it was not possible to confirm whether this result could be applied to patients with mild disease. Moreover, since these serum markers were not related to the application ofmechanical ventilation, they did not help determinethe timing of initiation of mechanical ventilation in a clinical setting.

Irrespective ofthese limitations, we determined that circulating sIL-2R wasassociated with mortality and disease severity asindicated by thePaO₂/FiO₂ratio. This knowledgecanshed light onthe cellular mechanism and immune regulation involvedin the pathogenesis ofCOVID-19; furthermore, it cangive impetusfortreatment options in the future. A large cohort study is needed to validate our findings.

In summary, the most relevant result of this study was that sIL-2R was significantly associated with mortality and disease severity in COVID-19 patients with respiratory failure, even after adjusting for several variables. Considering this association between the serum level of sIL-2R and the clinical outcome in COVID-19 patients with respiratory failure, sequential surveillance of sIL-2R and close observation would be needed.

Patient Recruitment

Patient data were retrospectively collected from the ICU of a tertiary hospital in South Korea, from February 2020 to April 2021. We reviewed the medical records of patients who were confirmed to be COVID-19-positive by the detection of viral RNA in their nasopharyngeal secretions or sputum, using a real-time reversetranscriptase polymerase chain reaction test.Patients who were diagnosed with respiratory failure and received high flow nasal cannula (HFNC) oxygen therapy or mechanical ventilation were included.Respiratory failure was defined as a PaO₂/FiO₂ratio (the ratio of partial pressure of oxygen in the arterial blood, PaO₂, to the fraction of inspired oxygen, FiO₂), of less than 300.

All patients confirmed to be COVID-19-positive were treated as per the treatment protocol released by Society of Critical Care Medicine [29]. Patients underwent laboratory tests including CRP, procalcitonin, IL-6, and sIL-2R at the time of admission (Day 0), and on the 7th day of hospitalization (Day 7). To measure the severity of disease, we calculated the Acute Physiology And Chronic Health Evaluation II (APACHE II) score at the time of admission, and sequential organ failure assessment (SOFA) score at the time of admission and on Day 7.

Data collection

All data were collected from electronic medical records of patients. The following clinical and laboratory data on Day 0 and Day 7were collected: age; sex; comorbidities; prognosis; P/F ratio; baseline serum markers including CRP, procalcitonin, IL-6, and soluble IL 2 receptor; SOFA score; and APACHE II score.

Statistical analysis

Continuous variables are reported as median with interquartile rages (IQR, 25^th to 75^th percentiles) while categorical variables are reported as numbers (percentage). Categorical variables were compared using the chi-square test and continuous variables using either the independent t-test or Mann Whitney U test, according to the normality of distribution.

Bivariate correlations were made by two-tailed Pearson correlation tests and survival curves were shown using Kaplan-Meier analysis. We further investigated the relationship between clinical parameters and mortality using Cox proportional hazard models, with stepwise selection of variables that were found to be significant on univariate regression analysis. In all cases, p values < 0.05 were considered statistically significant. All statistical analyses were performed using IBM SPSS Statistics version 25.0 (IBM Corp., Armonk, N.Y., USA)

Ethics

This research protocol was approved by the Institutional Review Board of Severance Hospital, South Korea (IRB No. 4-2021-0305). The study design was approved by the appropriate ethics review board, and the requirement to obtain informed patient consent was waived due to the retrospective nature of the study. The study protocol is performed in accordance with the relevant guidelines.

Author Contributions:

Study Conception and Design, HJ Jang and SH Lee; Acquisition of Data, HJ Jang, AY Leem, YS Kim, MS Park, SH Lee, and JY Ahn; Analysis and Interpretation of Data, HJ Jang, KS Chung,JY Ahn, JY Jung, and SH Lee; Drafting of Manuscript, HJ Jang, MS Park, YS Kim and SH Lee; Technical Support and Consulting, SH Lee, KS Chung, YA Kang and JY Jung.All authors have read and approved the final manuscript.

Financial/nonfinancial disclosures: None declared.

Role of the sponsors: This research was not sponsored.

Other contributions: None to declare.

Summary conflict of interest statement: All authors declare no conflict of interest.

Funding: This research received no external funding.

Notation of prior abstract publication/presentation: The abstract of this study has not been published/presented before.

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No competing interests reported.

Soluble IL-2R Levels Predict in-Hospital Mortality in COVID-19 Patients with Respiratory Failure

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