key: cord-0847437-wno9q5qb authors: Zeng, Hao-Long; Zhang, Bo; Wang, Xu; Yang, Qing; Cheng, Liming title: Urinary trace elements in association with disease severity and outcome in patients with COVID-19 date: 2020-12-30 journal: Environ Res DOI: 10.1016/j.envres.2020.110670 sha: 3077ed1ddbe7d7eb8285280c3a430cc723e346b3 doc_id: 847437 cord_uid: wno9q5qb BACKGROUND: The dynamics of urinary trace elements in patients with COVID-19 still remains to be investigated. METHODS: A retrospective study was performed on a cohort of 138 confirmed COVID-19 patients for their urinary levels of essential and/or toxic metals including chromium, manganese, copper, arsenic, selenium, cadmium, mercury, thallium and lead according to the different disease severity (severe or non-severe) and outcome (recovered or deceased). RESULTS: Urinary concentrations of chromium, manganese, copper, selenium, cadmium, mercury and lead after creatinine adjustment were found to be higher in severe patients than the non-severe cases with COVID-19. And among the severe cases, these elements were also higher in the deceased group than the recovered group. When the weeks of the post-symptom onset were taken in account, the changes of these urinary elements were existed across the clinical course since the disease onset. These urinary elements were found to be mostly positively inter-correlated, and further positively correlated with other laboratory inflammatory parameters including serum cytokines (IL-1B, IL2R, IL6, IL8, IL10, TNFα), ferritin, and neutrophil count and white blood cell count. As a independently predictive factor, urinary creatinine-adjusted copper of ≥ 25.57 μg/g and ≥ 99.32 μg/g were associated with significantly increased risk of severe illness and fatal outcome in COVID-19, respectively. CONCLUSIONS: These results suggest abnormities in urinary levels of the trace metals were tightly associated with the severe illness and fatal outcome of COVID-19. The outbreak of coronavirus disease 2019 that caused by severe acute 54 respiratory syndrome coronavirus 2 (SARS-CoV-2) is evolving rapidly worldwide [1] . 55 Since December, 2019, there were more than 7.7 million confirmed cases and more 56 than 420 000 deaths reported globally, as of June 13, 2020. WHO declared this 57 outbreak a pandemic on March 11, 2020. 58 It is now undeniable that the managed care of patients with COVID-19 encompasses 59 the identification of clinical and laboratory parameters, enabling accurate risk 60 stratification of progressing toward severe or critical disease [2] . Urinary tract 61 involvement is commonplace in patients with COVID-19, and that progressive 62 deterioration of renal function shall be considered an unfavorable prognostic factor [3] . 63 The clinical significance of urinalysis for predicting the severity of coronavirus 64 disease 2019 has been commonly reported recently [2, 4] . However, the 65 urinary levels of trace metals in patients with COVID-19 still remains to be 66 investigated. The main trace elements of general concerns are the most toxic ones such as arsenic 68 (As), cadmium (Cd), lead (Pb), mercury (Hg), thallium (Tl) and chromium (Cr) 69 laboratory, and also certified by College of American Pathologist (CAP). Internal 153 quality assessment (IQA) was carried out during analysis by using the traceable 154 ClinChek urine materials RECIPE, Germany) . Urine controls were 155 tested following every twenty specimens to ensure quality throughout screening. The 156 Z-score was calculated, and the values within the +2 to -2 range were satisfactory and 157 indicated analytical trueness. External quality assessment (EQA) was carried out by 158 participation in the College of American Pathologists (CAP) proficiency program 159 (https://www.cap.org/laboratory-improvement/proficiency-testing ). Data analysis 161 Descriptive statistics were performed with continuous variables estimated as median 162 and interquartile range (IQR), and categorical variables summarized as frequencies 163 and proportions. The normal range of each trace elements were described as we 164 recently reported [6] . Considering the distributions of the elements tested by the 165 Kolmogorov-Smirov test, were mostly not normal, The nonparametric tests were used 166 in our data analysis. The Mann-Whitney U test was used to compare the results 167 between different disease severities and different outcomes, respectively. The 168 spearman correlation test and its statistical significance were used to assess the 169 correlation between the different elements. The urinary trace elements were tested for 170 their discriminative power in determining the predictive criteria for severe illness and 171 fatal outcome by calculating the area under the receiver operating characteristic (ROC) 172 curve. Sensitivity and specificity were calculated according to ROC curves for each 173 parameter. Multivariate analyses were performed using a logistic regression model to 174 adjust for the effects from age and sex. For data analysis, individual results below the 175 limit of quantification (LoQ) were replaced by the (LoQ/2) value. All analyses were performed using SPSS version 22.0 (SPSS, Chicago, USA) and p < 0.05 was 177 considered statistically significant. The present study included a total of 138 hospitalized patients with confirmed 181 COVID-19. The median age was 61.5 years old (IQR: 55-68), and 59 ( vs 7.3 pg/ml), and neutrophil (7.43 vs 3.25, × 10 9 /L) and WBC (9.17 vs 5.64, × 10 9 /L), 205 and showed lower levels of urinary creatinine (4241 vs 9299 µmol/L) and lymphocyte 206 (0.78 vs 1.64, × 10 9 /L). A total of 210 urine specimens were collected from the 138 COVID-19 patients. Among them, 36 patients had at least two urine specimens at different time points. The urinary analysis including urinary protein qualification and urinary creatinine 210 determination were performed for all these samples. In comparison with non-severe 211 group, the severe group showed higher percentage of proteinuria incidence (62.4% 212 vs 12.0%), altogether both group collectively showed 43.8% of proteinuria incidence 213 in all the COVID-19 patients ( Table 2) . Urinary creatinine was found to be much Among the increased urinary elements mentioned above, chromium increased in urine 324 has been reported to be associated with impairment of renal function in the 325 hypertensive population [7] . Chromium is thought as a "hypoglycemic metal element", which could improving glucose tolerance through insulin resistance [12, 13] . Drastic 327 increase of urinary chromium in patients with diabetes [12] , and also in non-diabetic, 328 normotensive subjects with increased insulin resistance has been confirmed [14] . The 329 increased has been shown to actually stem from increased absorption of chromium creatinine; Cr, chromium; Mn, manganese; Cu, copper; As, arsenic; Se, selenium; Cd, 544 cadmium; Hg, mercury; Tl, thallium; Pb, lead. A Novel Coronavirus from Patients with Pneumonia in China Abbreviations: Cr, chromium; Mn, manganese; Cu, copper; As, arsenic; Se, selenium; Cd, cadmium; Hg, mercury; Tl, thallium The authors thank all the medical care workers who participated in the sample 417 collection. The work was supported by National Natural Science Foundation of China 418 Bonetti, G., et al., Urinalysis parameters for predicting severity in coronavirus disease 427 2019 . Clin Chem Lab Med, 2020.