Serum trace elements levels and clinical outcomes among Iranian COVID-19 patients

  • Author Footnotes
    † Yahya Yahyavi and Ozra Bagher Pour contributed equally to this work.
    Ozra Bagher Pour
    Footnotes
    † Yahya Yahyavi and Ozra Bagher Pour contributed equally to this work.
    Affiliations
    Tuberculosis and Lung Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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  • Author Footnotes
    † Yahya Yahyavi and Ozra Bagher Pour contributed equally to this work.
    Yahya Yahyavi
    Footnotes
    † Yahya Yahyavi and Ozra Bagher Pour contributed equally to this work.
    Affiliations
    Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
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  • Abbas Karimi
    Correspondence
    Correspondence to: Abbas Karimi, Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences. Golgasht St., Tabriz, East Azerbaijan, Iran. Tel/fax: +98 41 33355789 - Postal code: 5166614756. ORCID ID: https://orcid.org/0000-0002-1172-8502
    Affiliations
    Tuberculosis and Lung Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

    Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
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  • Amir Mehdi Khamaneh
    Affiliations
    Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
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  • Mortaza Milani
    Affiliations
    Department of Nanotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
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  • Majid Khalili
    Affiliations
    Tuberculosis and Lung Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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  • Akbar Sharifi
    Correspondence
    Corresponding author. Akbar Sharifi, Tuberculosis and Lung Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran, ORCID ID: http://orcid.org/0000-0001-8808-2028
    Affiliations
    Tuberculosis and Lung Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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  • Author Footnotes
    † Yahya Yahyavi and Ozra Bagher Pour contributed equally to this work.
Open AccessPublished:August 25, 2021DOI:https://doi.org/10.1016/j.ijid.2021.08.053

      Highlights

      • 1
        We studied Serum trace element levels that were not associated with disease severity
      • 2
        Zn serum levels were strongly associated with patient outcomes
      • 3
        Zn level can be considered a strong indicator for patients’ outcomes

      Abstract

      Objectives: The relationship between immunity and trace elements levels is well known. We aimed to estimate the association of serum trace elements with severity and outcomes in the Coronavirus Disease-2019 (COVID-19) patients.
      Methods: In this single-centered, prospective, observational study, we enrolled 114 patients admitted to severe intensive care units (ICUs) and corresponding 112 sex and aged-matched non-ICU ward patients. Demographic data, clinical characteristics, and outcomes were all collected. We analyzed serum levels of zinc (Zn), copper (Cu), selenium (Se), and manganese (Mn) in both severity groups.
      Results: The serum levels of Cu, Se, and Mn in both groups were within the normal range while Zn serum levels were lower than normal values. Based on these findings, Zn, Cu, Se, and Mn serum levels were not associated with disease severity (P > 0.05), while we found Zn serum levels were strongly associated with patient outcomes (P = 0.005). Our results indicated lower Mn serum levels were associated with age more than 55 years (P= 0.006). Our results were not in favor of a causal relationship between serum trace elements levels and disease severity.
      Conclusion: We found Zn level to be a strong indicator for patients’ outcomes that can be considered for monitoring patient prognosis. Nutritional measures or supplementation can help reduce poor outcomes caused by low Zn levels in Iranian COVID-19 patients.

      Keywords

      Introduction

      Human beings have experienced three major epidemics caused by coronaviruses including Severe Acute Respiratory Syndrome (SARS-2003), Middle East Respiratory Syndrome (MERS-2012), and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV 2), which has infected more than 155 million, killing over 3.2 million people globally as of May 5, 2020 (
      • Morfeld P
      • Timmermann B
      • Groß VJ
      • Lewis P
      • Erren TC.
      COVID-19: Wie änderte sich die Sterblichkeit?–Mortalität von Frauen und Männern in Deutschland und seinen Bundesländern bis Oktober 2020.
      ,

      Organization. WH. World Health Organization.Novel Coronavirus (2019-nCoV). 2020. Available from: https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200121-sitrep-1-2019-ncov.pdf.

      ). COVID-19 first appeared in December 2019 in Wuhan, China, and is now considered a public health emergency of international concern. SARS-CoV-2 genome consists of a positive-sense single-stranded RNA virus linked with a nucleoprotein inside a capsid containing matrix protein as well as a hemagglutinin-esterase (HE) protein found on some coronaviruses (
      • Jiang S
      • Xia S
      • Ying T
      • Lu L.
      A novel coronavirus (2019-nCoV) causing pneumonia-associated respiratory syndrome.
      ,

      Khaerunnisa S, Kurniawan H, Awaluddin R, Suhartati S, Soetjipto S. Potential inhibitor of COVID-19 main protease (Mpro) from several medicinal plant compounds by molecular docking study. 2020.

      ,

      Organization. WH. World Health Organization.Novel Coronavirus (2019-nCoV). 2020. Available from: https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200121-sitrep-1-2019-ncov.pdf.

      ,
      • Wu F
      • Zhao S
      • Yu B
      • Chen Y-M
      • Wang W
      • Song Z-G
      • et al.
      A new coronavirus associated with human respiratory disease in China.
      ). The clinical manifestations of the disease usually include fever, headache, cough, gastrointestinal manifestations such as diarrhea, vomiting, and abdominal pain, and dyspnea. The acute coronavirus infectious disease is characterized by pneumonia, lymphocytopenia, exhaustion of lymphocytes, and cytokine storm syndrome in severe forms of COVID-19 that is manifested with increased plasma levels of cytokines (IL2, IL7, and IL10), granulocyte colony-stimulating factor (G-SCF), 10 kD interferon-gamma-induced protein (IP10), monocyte chemoattractant protein-1 (MCP1), macrophage inflammatory protein 1-α (MIP1A), and interferon-alpha (TNF-α) (
      • Dietz W
      • Santos-Burgoa C.
      Obesity and its implications for COVID-19 mortality.
      ,
      • Kong R
      • Yang G
      • Xue R
      • Liu M
      • Wang F
      • Hu J
      • et al.
      COVID-19 Docking Server: A meta server for docking small molecules, peptides and antibodies against potential targets of COVID-19.
      ,
      • Wong SH
      • Lui RN
      • Sung JJ.
      Covid-19 and the digestive system.
      ).
      Several micronutrients including vitamins and trace elements are required for the normal functioning of the immune system to protect the cells from oxidative stress (
      • Lee YH
      • Bang E-S
      • Lee J-H
      • Lee J-D
      • Kang DR
      • Hong J
      • et al.
      Serum concentrations of trace elements zinc, copper, selenium, and manganese in critically ill patients.
      ). The major trace elements viz selenium (Se), zinc (Zn), copper (Cu), and manganese (Mn) holding immunomodulatory effects are components of antioxidant enzymes that can inhibit viral replication in the host cells and therefore have antiviral activity (
      • Chaturvedi U
      • Shrivastava R
      • Upreti R.
      Viral infections and trace elements: a complex interaction.
      , (
      • Jayawardena R
      • Sooriyaarachchi P
      • Chourdakis M
      • Jeewandara C
      • Ranasinghe P.
      Enhancing immunity in viral infections, with special emphasis on COVID-19: A review.
      ). Unbalanced dietary habits may predispose individuals to viruses and other infections (
      • Thurnham DI.
      Micronutrients and immune function: some recent developments.
      ). Maintaining adequate micronutrient balance may boost the host's immune response and protect him/her against viral infections (
      • Razzaque MS.
      COVID-19 pandemic: can maintaining optimal zinc balance enhance host resistance?.
      ). Assessing trace elements levels in COVID-19 patients can provide a more robust and comprehensive approach for combating this devastating disease.

      Materials and Methods

       Patients

      This prospective, cohort, observational study was conducted at Imam Reza hospital of Tabriz University of Medical Sciences, Tabriz, Iran. A total of 226 COVID-19 patients, confirmed by the nasopharyngeal swab tested with reverse transcription polymerase chain reaction (admitted from October 10 to December 10, 2020), were enrolled in the study. Pregnant patients and patients taking any form of dietary supplements/multivitamins or trace elements were excluded from the study. Patients were categorized into two groups: severe and non-severe patients based on the intensive care unit (ICU) and non-ICU ward hospitalization. Each severity group was individually matched for age and sex. This study was approved by the Ethics Committee of Tabriz University of Medical Sciences, Iran (Ref No: IR.TBZMED.REC.1399.711). All the procedures involving human samples conformed to the principles outlined in the Declaration of Helsinki. Participation was voluntary, and written informed consent was obtained from all patients or their legal guardians.

       Blood collection and trance elements measurement

      Eight milliliters of blood were collected from each participant. After centrifugation for 10 min at 3000 g, 4 mL serum was obtained. Two mL of serum was used for determining Se and Mn concentrations, and the remaining 2 mL was used for Zn and Cu measurement. All necessary precautions were taken in the handling of the specimens collected as per standard laboratory guidelines considering COVID-19 complications. We measured serum Zn and Cu by Randox colorimetric assays (Randox Laboratories Ltd., Crumlin, UK). The reference range for serum Cu was 70-140 μg/dL, and for Zn was 72.6-127 μg/dL in men and 77.0-114 μg/dL in women according to the kit instruction manual. Serum Se and Mn concentrations were determined by graphite furnace atomic absorption spectrophotometry (GFAAS), which is a type of atomic spectroscopic technique as described (
      • Krawczyk-Coda M.
      Determination of Selenium in Food Samples by High-Resolution Continuum Source Atomic Absorption Spectrometry After Preconcentration on Halloysite Nanotubes Using Ultrasound-Assisted Dispersive Micro Solid-Phase Extraction.
      ). Serum levels ranging from 0.6 to 4.3 μg/L were considered normal reference values for Mn (
      • Flora SJS.
      Chapter 29 - Metals.
      ). Regarding Se, normal reference values were considered to be 70 to 150 μg/L, the most reference values given in the literature.

       Statistical analysis

      Statistical analysis was performed using IBM SPSS version 21.0 (IBM SPSS Statistics, ARMONK, New York, USA). Data were expressed as mean ± standard deviation (SD) for continuous variables or numbers, whereas categorical variables were described as their respective percentages. The difference in serum trace elements levels between subgroups was analyzed using one-way analysis of variance (ANOVA) and unpaired t-tests. Moreover, Pearson's chi-squared test was used to analyze the significance of association between categorical variables. A P value < 0.05 was considered statistically significant.

      Results

      The demographic and clinical characteristics of the participants are presented in Table 1. The mean ages of patients in ICU and non-ICU ward groups were 56 ± 20.6 and 56.7 ± 16.3 years, respectively. Comparison of major symptoms between ICU and non-ICU ward patients showed no significance except for chest pain, fever, and lower chest wall indrawing (< 0.05). Five patients in the non-ICU ward group had conjunctivitis. Moreover, none of the patients with COVID-19 showed skin rash or ulcers, lymphadenopathy, or hemorrhage. In comparison with non-ICU ward patients, the ICU cases had elevated heart rate (94.62 ± 1.58 vs. 87.88 ± 1.57) with low oxygen saturation level (76.05 ± 1.08 vs. 81.7 ± 0.88) that was significant (P < 0.05). The difference between the two severity groups for the remaining cardiovascular parameters was not statistically significant. The ICU cases also showed a significantly higher frequency of obesity (9 (81.81%) vs. 2 (18.18%), P= 0.049) and dementia (20 (76.92%) vs. 6 (23.07%), P= 0.005). Other comorbidities among both severity groups were not significant. The serum levels of trace elements in patients are presented in Table 2. Cu and Zn levels were found to be 95.74 ± 1.25 and 67.87 ± 1.12 μg/dL, respectively. Se and Mn levels were reported 126.61 ± 2.05 and 2.58 ± 0.069 μg/L, respectively. Our findings indicated that in ICU patients compared to non-ICU ward patients, serum Zn levels (67.3 ± 1.79 vs. 68.42 ± 1.35, P= 0.619) and Cu levels (94.58 ± 1.97 vs. 96.88 ± 1.57, P= 0.362) were low though the difference was not significant. The serum values for Se and Mn in both groups were reported as 130.19 ± 3.19 versus 123.06 ± 2.58 (P= 0.084) and 2.68 ± 0.11 versus 2.49 ± 0.08 (P= 0.167), respectively, but the difference was not significant. According to our data, low Zn levels (69.66 ± 1.34 vs. 62.43 ± 1.81, P= 0.005) were found to be associated with death among COVID-19 patients (Table 3). Cu, Se, and Mn values were not associated with patient outcomes (Table 3). During this study, 170 (75.22%) patients were discharged from the hospital and 56 (24.78%) patients died. Of the 56 deaths, 27 (48.2%) were female and 29 (51.8%) were male. Regarding the association of trace elements with age variable, a significant difference was found in Mn levels of patients aged <55 and >55 years (2.80 ± 1.11 vs. 2.38 ± 90, P= 0.006). For the remaining, this association was not significant (Table 4). Cu and Se levels did not display any difference between males and females (P > 0.05). Zn levels were significantly higher in men than women (71.36 ± 18.83 vs. 64.31 ± 13.80, P= 0.002) and Mn levels were significantly lower in men compared to women (2.44 ± 96 vs. 2.72 ± 1.07, P- 0.047) (Table 5).
      Table 1Demographic and clinical characteristics of the patients with COVID-19
      ParameterAll patients (n=226)ICU group (n = 112)Non-ICU group (n= 114)P-value
      SexMale11456 (50%)58 (50.9)0.895
      Female11256 (50%)56 (49.2)
      Age (mean ± SD)56.36 ± 18.5456 ± 20.656.72 ± 16.30.34
      OutcomeDeceased56 (24.8%)38 (33.9%)18 (15.8%)0.002
      Recovered170 (75.2%)74 (66.1%)96 (84.2%)
      Initial symptomsHR (beats per minute)91.2 ± 1.1294.62 ± 1.5887.88 ± 1.570.003
      RR (breaths per minute)21.81 ± 0.4422.01 ± 0.5221.57 ± 0.730.622
      Systolic BP (mmHg)123.16 ± 1.35124.33 ± 2.21122.2 ± 1.640.439
      Diastolic BP (mmHg)75.17 ± 0.974.5 ± 1.5476.04 ± 10.405
      Oxygen saturation (spo2)78.91 ± 0.7176.05 ± 1.0881.7 ± 0.880.000
      Fever7427 (37.5%)45 (62.5%)0.013
      Coughing18392 (51.39%)87 (48.6%)0. 281
      Coughing with sputum production175 (29.41%)12 (70.58%)0.084
      Coughing; bloody sputum/haemoptysis106 (66.6%)3 (33.3%)0.295
      Sore throat13262 (48%)67 (52%)0.604
      Runny nose (Rhinorrhoea)6631 (47%)35 (53%)0.617
      Ear pain2516 (64%)9 (36%)0.126
      Wheezing7843 (56.57%)33 (43.42%)0.133
      Chest pain14478 (55.31%)63 (44.68%)0.026
      Myalgia20099 (50.25%)98 (49.74%)0.585
      Arthralgia14741 (27.89%)106 (72.1%)0.169
      Fatigue18794 (50.81%)91 (49.18%)0.423
      Dyspnea216110 (50.92%)106 (49.07%)0.605
      Lower chest wall indrawing7655 (74.32%)19 (25.67%)0
      Headache12160 (50.42%)59 (49.57%)0.784
      Abdominal pain5425 (46.29%)29 (53.7%)0.583
      Vomiting/Nausea9244 (48.35%)47 (51.64%)0.766
      Diarrhoea156 (40%)9 (60%)0.444
      Conjunctivitis50 (0%)5 (100%)0.025
      Skin rash000
      Skin ulcer000
      Lymphadenopathy000
      Bleeding/Haemorrhage000
      ComorbiditiesChronic cardiac disease4626 (57.7%)19 (42.2%)0.218
      Obesity119 (81.81%)2 (18.18%)0.049
      Chronic pulmonary disease179 (56.25%)7 (43.75%)0.579
      Diabetes without complications3111 (35.48%)20 (64.51%)0.092
      Diabetes with complications1711 (68.75%)5 (29.41%)0.111
      Asthma127 (63.63%)4 (36.36%)0.390
      Chronic kidney disease5538 (70.37%)16 (29.62%)0
      Rheumatic disorder32 (66.66%)1 (33.33%)0.551
      Moderate or severe liver disease43 (75%)1 (25%)0.556
      Mild liver disease114 (36.36%)7 (63.63%)0.206
      Dementia2620 (76.92%)6 (23.07%)0.005
      Chronic neurological disorder81 (12.5%)7 (87.5%)0.427
      Smoking5127 (52.94%)24 (47.05%)0.848
      Malignant neoplasm62 (33.33%)4 (66.66%)0.420
      Chronic hematologic disease62 (33.33%)4 (66.66%)0.420
      Other relevant risk factor (Hypertension)7945 (56.96%)34 (43.03%)0.103
      Categorical data such as sex and outcome are represented as n (%). All other data are represented as mean ± SD.
      Table 2Serum levels of Zn, Cu, Se, and Mn in patients with COVID-19 (severe and non-severe groups)
      ElementsNormal rangeSeverity groupP-value
      AllICUNon-ICU
      Cu70-140 μg/dL95.74 ± 1.2594.58 ± 1.9796.88 ± 1.570.362
      ZnMen: 72.6-127 Women: 77.0-114 μg/dL67.87 ± 1.1267.3 ± 1.7968.42 ± 1.350.619
      Se70 to 150 μg/L126.61 ± 2.05130.19 ± 3.19123.06 ± 2.580.084
      Mn0.6 to 4.3 μg/L2.58 ± 0.0692.68 ± 0.112.49 ± 0.080.167
      P-values are for comparison between ICU and non-ICU ward groups. Cu: copper, Zn: zinc, Se: selenium, Mn: manganese.
      Table 3Serum trace elements levels by patients’ outcomes (recovered vs. deceased)
      ElementsOutcomesP-value
      RecoveredDeceased
      Cu95.12 ± 1.4397.64 ± 2.630.389
      Zn69.66 ± 1.3462.43 ± 1.810.005
      Se125.77 ± 2.41129.15 ± 3.910.481
      Mn2.59 ± 0.072.57 ± 0.140.900
      Cu: copper, Zn: zinc, Se: selenium, Mn: manganese.
      Table 4Cu, Zn, Se, and Mn serum levels by age groups
      ElementsAge (years)P-value
      < 55 (n = 109)≥ 55 (n = 117)
      Zn68.7 ± 16.1867.1 ± 17.510.36
      Cu96.01 ± 21.5595.5 ± 16.2150.67
      Mn2.8047 ± 1.118012.38 ± 900.006
      Se128.92 ± 34.01124.48 ± 27.370.23
      Zn: zinc, Cu: copper, Mn: manganese, Se: selenium.
      Table 5Serum trace elements levels by sex
      ElementsAge (years)P-value
      Male (n = 114)Female (n = 112)
      Zn71.36 ± 18.8364.31 ± 13.800.002
      Cu97.77 ± 17.4793.69 ± 20.190.106
      Mn2.44 ± 962.72 ± 1.070.047
      Se128.40 ± 31.29124.80 ± 30.230.382
      Zn: zinc, Cu: copper, Mn: manganese, Se: selenium.

      Discussion

      The latest evidence on coronaviruses indicates that nutritional and metabolic derangements are associated with disease severity and susceptibility to infection (
      • Jayawardena R
      • Sooriyaarachchi P
      • Chourdakis M
      • Jeewandara C
      • Ranasinghe P.
      Enhancing immunity in viral infections, with special emphasis on COVID-19: A review.
      ,
      • Lv Y
      • Chen L
      • Liang X
      • Liu X
      • Gao M
      • Wang Q
      • et al.
      Association between iron status and the risk of adverse outcomes in COVID-19.
      ,
      • Singer P.
      Nutritional and metabolic management of COVID-19 intensive care patients.
      ,
      • Zeng HL
      • Zhang B
      • Wang X
      • Yang Q
      • Cheng L.
      Urinary trace elements in association with disease severity and outcome in patients with COVID-19.
      ). In this study, we measured serum trace elements status in severe and non-severe COVID-19 patients. Based on the findings, Zn, Cu, Se, and Mn levels were not associated with COVID-19 severity while Zn level was strongly associated with patient outcomes.
      Zn is needed for the proliferation and function of NK cells, macrophages, neutrophils, T and B cells, production of cytokines, and inhibition of reactive oxygen species (
      • Iddir M
      • Brito A
      • Dingeo G
      • Fernandez Del Campo SS
      • Samouda H
      • La Frano MR
      • et al.
      Strengthening the immune system and reducing inflammation and oxidative stress through diet and nutrition: considerations during the COVID-19 crisis.
      ,
      • Rahman MT
      • Idid SZ.
      Can Zn be a critical element in COVID-19 treatment?.
      ). Due to its direct antiviral properties, Zn is beneficial for disease prevention. Development and maintenance of both innate and adaptive immune systems require proper intake of Zn; hence its deficiency causes dysfunction in lymphocyte maturation, impairment in cellular communication by cytokines, and weakness in innate immunity (
      • Maares M
      • Haase H.
      Zinc and immunity: An essential interrelation.
      ). Our findings showed Zn serum levels in both severity groups were less than the normal reference range and were strongly associated with patients' mortality, indicating a potential role for Zn in COVID- 9 pathogenesis. In addition, we found gender differences in serum Zn levels among COVID-19 patients.
      Se is an important component of some enzymes and works together with vitamin E to prohibit free radicals production (
      • Jamaati H
      • Dastan F
      • Tabarsi P
      • Marjani M
      • Saffaei A
      • Hashemian SM.
      A fourteen-day experience with coronavirus disease 2019 (COVID-19) induced acute respiratory distress syndrome (ARDS): an Iranian treatment protocol.
      ). Se deficiency negatively impacts immune system function and increases viral replication and mutation rates (
      • Harthill M.
      Micronutrient selenium deficiency influences evolution of some viral infectious diseases.
      ). Recently, lower Se levels have been reported to be associated with COVID-19 (
      • Majeed M
      • Nagabhushanam K
      • Gowda S
      • Mundkur L.
      An exploratory study of selenium status in healthy individuals and in patients with COVID-19 in a south Indian population: The case for adequate selenium status.
      ) and also with the mortality risk of patients (
      • Moghaddam A
      • Heller RA.
      ). Our findings were not in agreement with those reports. We found a positive trend between Se levels and ICU patients. It seems that the critically ill patients possibly received Se supplement before admission to ICU ward that were not recorded due to the recall bias.
      Cu is an essential trace element that is needed for protecting DNA from oxidative stress (
      • Karimi A
      • Majidzadeh AK
      • Madjd Z
      • Akbari A
      • Habibi L
      • Akrami SM.
      Effect of Copper Sulfate on Expression of Endogenous L1 Retrotransposons in HepG2 Cells (Hepatocellular Carcinoma).
      ,
      • Karimi A
      • Sheervalilou R
      • Kahroba H.
      A New Insight on Activation of Human Endogenous Retroviruses (HERVs) in Malignant Melanoma upon Exposure to CuSO4.
      ,
      • Uriu-Adams JY
      • Keen CL.
      Copper, oxidative stress, and human health.
      ). Cu deficiency is associated with immune system dysfunction, enhanced rate of infections, and TNF-ɑ-induced lung chronic inflammation (
      • Bonham M
      • O'Connor JM
      • Hannigan BM
      • Strain J.
      The immune system as a physiological indicator of marginal copper status?.
      ,
      • Liu L
      • Geng X
      • McDermott J
      • Shen J
      • Corbin C
      • Xuan S
      • et al.
      Copper deficiency in the lungs of TNF-α transgenic mice.
      ). Cu can also inhibit RNA replication in COVID-19 (
      • Andreou A
      • Trantza S
      • Filippou D
      • Sipsas N
      • Tsiodras S.
      COVID-19: The potential role of copper and N-acetylcysteine (NAC) in a combination of candidate antiviral treatments against SARS-CoV-2.
      ). In the current study, the patients’ Cu values fell within the normal range and were not associated with disease severity, patient outcome, sex, and age.
      Mn plays an essential role in many cellular processes including enzymatic function (
      • Kehl-Fie TE
      • Skaar EP.
      Nutritional immunity beyond iron: a role for manganese and zinc.
      ). There is little information regarding Mn effect on immune development and COVID-19 pathogenesis. In a recently published study, liver dysfunction in severe COVID-19 was suspected to be associated with higher urinary Mn levels (
      • Zeng HL
      • Zhang B
      • Wang X
      • Yang Q
      • Cheng L.
      Urinary trace elements in association with disease severity and outcome in patients with COVID-19.
      ). Our results indicated lower Mn levels were associated with age more than 55 years, indicating feeding this group with a low Mn diet and a possible susceptibility to disease.

      Conclusion

      On the whole, our results were not in favor of a causal relationship between trace elements levels and disease severity. We identified Zn level as a strong indicator for patients’ outcomes that can be considered for monitoring of patients’ prognosis. Future studies on a larger population regarding trace elements levels at hospital admission time and after hospitalization would be valuable and helpful in the evaluation of the dynamic changes in patients with COVID-19. Finally, nutritional measures or supplementation may help reduce poor outcomes caused by this virus in Iranian patients.

      Funding

      This project was financially supported by Tuberculosis and Lung Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran (Grant/Award Number: 65697).

      Ethics approval

      This study was performed in line with the principles of the Declaration of Helsinki. It was approved by the Ethics Committee of Tabriz University of Medical Sciences, Iran (Ref No: IR.TBZMED.REC.1399.711).

      Availability of data and materials

      All data are available via the corresponding author.

      Authors’ contributions

      A.K. and A.S.:Conceptualizaion and design of the study; A.K., O.B., Y.Y., M.M., AM.K., and M.K.: Acquisition of data, analysis, and interpretation of data; O.B, Y.Y., and A.K.: Drafting the article; A.K. and A.S.: Critical revision of the article for important intellectual content.

      Conflicts of interest

      The authors have no conflicts of interest to declare relevant to the content of this article.

      Acknowledgments

      Our sincere thanks go to the Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.

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