key: cord-0773516-rxufqrkl
authors: Cheng, Anying; Hu, Liu; Wang, Yiru; Huang, Luyan; Zhao, Lingxi; Zhang, Congcong; Liu, Xiyue; Xu, Ranran; Liu, Feng; Li, Jinping; Ye, Dawei; Wang, Tao; Lv, Yongman; Liu, Qingquan
title: Diagnostic performance of initial blood urea nitrogen combined with D-Dimer levels for predicting in-hospital mortality in COVID-19 patients
date: 2020-07-23
journal: Int J Antimicrob Agents
DOI: 10.1016/j.ijantimicag.2020.106110
sha: 6a7113066c115a0e665ff3f92c6e63ce07ef840e
doc_id: 773516
cord_uid: rxufqrkl

The crude mortality rate in critical pneumonia cases of the new coronavirus disease (COVID-19) has reached 49%. This study aimed to test whether the levels of blood urea nitrogen (BUN) combined D-Dimer were predictors of in-hospital mortality in COVID-19 patients. We analyzed the clinical characteristics of 305 COVID-19 patients and compared them between the survivor and non-survivor groups. A total of 85 (27.9%) patients died, and 220 (72.1%) patients were discharged. Compared with discharged cases, non-survivor cases were older, and their BUN and D-Dimer levels were significantly higher (P<0.0001). LASSON and multivariable COX regression analyses identified BUN and D-Dimer as independent risk factors for poor prognosis. Kaplan-Meier analysis showed that elevated levels of BUN and D-Dimer had increased mortality compared with the other group (log-rank: P<0.0001). The area under the curve for BUN combined D-Dimer was 0.94 (95% CI 0.90–0.97), with a sensitivity of 0.85 and specificity of 91%. Based on BUN and D-Dimer levels on admission, a nomogram model was developed that showed good discrimination, with a C-index of 0.94. Together, initial BUN and D-Dimer levels were associated with mortality in COVID-19 patients. The combination of BUN>4.6 mmol/L and D-Dimer≥0.845 µg/L appears to identify patients of the high risk of in-hospital mortality; therefore, it may prove to be a powerful risk assessment tool for severe COVID-19 patients.

The novel coronavirus disease , which is caused by the SARS-CoV-2 virus infection, has been called an international public health emergency by the World Health Organization (WHO) [1, 2] . About 81% of patients with COVID-19 were mild.

However, 5% of critically ill patients progressed rapidly to acute respiratory distress syndrome and acute respiratory failure. The overall crude case fatality rate (CFR) was 2.3%, whereas, among critical cases, the crude mortality rate reached 49% [3] . At present, there is no established effective treatment for COVID-19. Early identification and supportive care can effectively reduce the incidence of persistent critical illness and in-hospital mortality. Hence, it is important to assess the factors related to COVID-19 to predict patient prognosis.

Blood urea nitrogen (BUN) is a nitrogenous end-product of protein metabolism and has been observed to be associated with mortality in various diseases. BUN represents a surrogate marker for predicting persistent organ failure after 48 hours of hospital admission, in addition to its role in the estimation of renal function [4, 5] . A multicenter study reported that BUN can independently predict mortality in critically ill patients admitted to the intensive care unit (ICU) [6] . Elevated BUN levels are a predictor of worse outcomes in patients with heart failure [7] . Recent studies have shown that the BUN to serum albumin ratio was an important prognostic factor of mortality and disease severity in aspiration pneumonia, hospital-acquired pneumonia, and community-acquired pneumonia (CAP) [8] [9] [10] . Moreover, serum albumin levels were also identified as prognostic factors for pneumonia diseases and demonstrated fair discriminative performance in the prediction of in-hospital mortality [11, 12] .

Therefore, we hypothesized that serum BUN levels could be associated with mortality among patients with COVID-19.

D-Dimer levels have a central role in diagnostic algorithms to rule out venous thromboembolism. Elevated plasma D-Dimer in adult CAP is associated with an increased inflammatory reaction and prognostic variable [13, 14] . Recent studies have reported that D-Dimer was significantly associated with the severity of COVID-19 [15, 16] . D-Dimer is a commonly tested laboratory marker in hospitalized patients.

However, the diagnostic performance of serum D-Dimer levels has not yet been reported among patients with COVID-19.

Although several studies have investigated the correlation between laboratory test parameters and disease severity of COVID-19 pneumonia so far, however, limited data are available regarding the association between laboratory data on admission and in-hospital outcomes in such patients. In the present study, we evaluated the association between serum BUN and D-Dimer levels on admission among patients with COVID-19 and in-hospital mortality, to improve its prognosis in the future.

This was a retrospective single-center study, which enrolled 305 patients from Committee, and written informed consent was obtained from patients involved before enrolment and data were collected retrospectively.

The demographic characteristics, clinical symptoms, laboratory data, and medications were extracted from the electronic medical records. Laboratory data consisted of complete blood count, liver and renal function test, examination of hemostasis parameters, measurement of high-sensitivity C-reactive protein (CRP), procalcitonin, and lactate dehydrogenase serum levels. Colorimetry was used to determine urea nitrogen concentration. The normal reference ranges of BUN were determined by our laboratory as 3.1-8.0 mmol/L in males and 2.6-7.5 mmol/L in females.

Categorical variables were described as frequency rates and percentages, and continuous variables were described using mean and SD for normally distributed variables and as median with IQR for non-normally distributed data. We used the Mann-Whitney U test or t-test to compare differences between survivors and non-survivors where appropriate. Proportions for categorical variables were compared using the chi-square test. A univariate and multivariate cox regression model was applied to screen the risk of death from factors such as a patient's clinical characteristics. Considering the sparse data and multicollinearity problem in the regression model, we used the least absolute shrinkage and selection operator (LASSO) analysis to select optimal risk factors for mortality. The discrimination capacity of the nomogram was measured by the concordance index (C-index), with the larger the C-index, the more accurate being the prognostic prediction. The

Kaplan-Meier method was used to assess the cumulative rate of mortality based on the median of BUN and D-Dimer, compared by the log-rank test. Receiver operating characteristic curve (ROC) analysis was performed to assess the accuracy of BUN and D-Dimer levels for predicting death. Stratified analyses were performed according to several major confounders. Age was stratified by the median value (65 years).

Estimated glomerular filtration rate (eGFR) was stratified to 90 mL/min/1.73 m 2 . The P for interaction was tested for multiplicative interactions. Tests were two-sided, and a P value less than 0.05 was considered statistically significant. All statistical analyses were performed using SPSS (version 23.0) or R (version 3.0.2).

Of with, at least, one of the comorbidities (e.g., hypertension, coronary heart disease, chronic obstructive pulmonary disease, and diabetes) was significantly higher in the death group ((79% in death group) vs. (49% in the survivor group, P<0.0001)).

However, no significant difference in signs and symptoms (e.g., fever, cough, nausea, and headache) was observed among these two groups. As for laboratory findings on admission, the levels of lymphocyte count, platelet count, albumin, and eGFR in the peripheral blood of the non-survivor patients were significantly lower at admission compared to the survivor patients (P <0.0001), while the levels of white blood cell count, neutrophil count, lactate dehydrogenase, CRP, interleukin-6 (IL-6), procalcitonin, BUN, and D-Dimer were significantly higher in the non-survivor group (P<0.0001). Antibiotics (95%), antiviral (96%), and glucocorticoids (44%) were the three most common medications among patients with COVID-19, and the percentage of treatment with mechanical ventilation, antiviral, corticosteroids, and immunoglobulin (P <0.0001) was significantly higher in the non-survivor group.

However, when specific antibiotics were considered, including cephalosporins (47%), quinolones (85%) and penicillins (15%). Arbidol (84%), lopinavir (10%), oseltamivir (21%), and Lianhua Qingwen granules (59%) were the commonly used antiviral medications.

In univariable regression analysis, the hazard of death was higher in elderly and male Table 2) . We also conducted a subgroup analysis for the age, eGFR, CRP, and comorbidity. Elevated BUN or D-Dimer was associated with an increased risk of mortality stratified by normal or abnormal eGFR, which was more evident among patients older than 65 years (Supplemental Figure 1A, B) .

Kaplan-Meier survival curves in patients within the hospital are provided in Figure 2 . There were significant differences in poor outcomes among these strata (P<0.0001). Moreover, the mortality incidence was significantly higher in strata 4 than strata 2 and 3 ( Figure 2C ).

The risk factors of BUN, D-Dimer, and CRP mentioned above were further analyzed by receiver operating characteristic (ROC) analysis to evaluate the predicting ability 

In our present study, we found that serum levels of BUN and D-Dimer were significantly higher in the non-survivor COVID-19 patients compared with the survivor cases. LASSO and multivariable cox regression analysis suggested that BUN and D-Dimer were independent predictive factors for in-hospital mortality.

Meanwhile, high levels of BUN and D-Dimer were associated with high mortality independent from other covariates and had a robust predictive ability for poor outcomes. Further analysis found BUN combined with D-Dimer had a stronger predictive ability, with an ideal sensitivity and specificity.

Several recent studies have investigated the serum markers to be closely associated with the severity of COVID-19 patients, such as neutrophil-to-lymphocyte ratio, D-Dimer, procalcitonin, IL-6, and lactate dehydrogenase [17] [18] [19] . However, only a few studies focused on the prognostic role of laboratory findings for mortality in these patients so far. We found more than 20 variables significantly related to mortality among the COVID-19 patients. Considering the sparse data and multicollinearity problem, the LASSO method was suitable for the regression of high-dimensional data and select optimal predictive features [20] . Finally, the BUN, D-Dimer, and CRP were screened as optimal risk factors associated with COVID-19 in-hospital mortality.

BUN is a renal function marker and is also a potential parameter of neurohormonal activity. A recent study has shown that high BUN levels at admission were robustly associated with adverse outcomes in critically ill patients admitted to ICU, even after correction for co-founders, including renal failure [21] . Besides, elevated levels of BUN are independent predictors of mortality in patients with heart failure or myocardial infarction [7, 22] . In line with previous studies, we found that elevated BUN was an independent risk factor for an unfavorable prognosis after adjusted eGFR, and had a high ability to predict mortality in patients with COVID-19. This finding is similar to that of a study that identified the relationship between higher serum BUN concentration and mortality in patients with H1N1-confirmed pneumonia [23] . Although serum creatinine is also a renal marker, it was not considered as a risk associated with worse prognosis in the COVID-19 patients in this study. The precise difference between BUN and creatinine to COVID-19 prognosis needs to be studied further.

Recently, D-Dimer was reported to be closely related to the severity of the COVID-19

patients, and when combined with IL-6 detection, it had the highest specificity and sensitivity for its early prediction [16] . The elevated level of D-Dimer was also associated with ICU admission and lower survival in CAP patients [13, 24] . The D-Dimer levels were lower in the survivors compared with the non-survivors at admission, with AUC 0.88 for predicting in-hospital mortality. Although the CRP also had almost the same clinical value to predict poor outcomes, the specificity of D-Dimer was higher than that of CRP. CRP is an acute-phase reactant associated with the severity of inflammation, and its serum levels are unstable and are susceptible to anti-inflammatory factors, especially in some COVID-19 patients who had been treated with antibiotics before the hospital admission. Also, previous studies indicated that there was some controversy about the prognostic significance of CRP in pneumonia. Some studies reported that CRP was associated with mortality in patients with CAP [25] . However, other studies showed non-significant correlation between CRP levels at admission and prognosis of CAP [26] . Moreover, our study found that prognostic factors, D-Dimer levels had a higher hazard rate than CRP for patients with COVID-19. Meanwhile, the BUN combined with D-Dimer had a higher AUC value and specificity than BUN or CRP alone or BUN combined CRP to predict the in-hospital mortality in patients with COVID-19. Therefore, we selected the parameters of BUN and D-Dimer for better prediction of in-hospital mortality among COVID-19 patients.

Based on BUN and D-Dimer levels and integrating patients , age on admission, we 

The initial serum BUN and D-dimer levels were associated with in-hospital mortality in patients with COVID-19. We developed a useful individualized nomogram that incorporated initial levels of BUN, D-Dimer, and patients , age, and can be conveniently used to predicate mortality in COVID-19 patients. The predictive model can help the clinicians to improve individual treatment, make timely clinical decisions, and make optimal use of limited clinical resources.

Funding: This study was supported by the grant from National Natural Science Foundation of P.R. China (No. 81800609).

The authors report no conflicts of interest in this work.

Tongji Hospital (TJ-IRB20200353). The consent to participate is not applicable because of this is a retrospective study.

BUN, blood urea nitrogen; CFR, crude case-fatality rate; ICU, intensive care unit; CAP, community-acquired pneumonia; LASSO analysis, least absolute shrinkage and selection operator analysis; eGFR, estimated of the glomerular filtration rate; C-index, concordance index; CRP, C-reactive protein; CI, confidence interval.

The datasets generated and analysed during the current study are available from the corresponding author on reasonable request. 

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