Introduction

Since the first known case was reported in December 2019, the World Health Organization (WHO) has declared the coronavirus disease 2019 (COVID-19) to be a nationwide pandemic. The severity of COVID-19 is connected to the body's immunity and the viral subtype of infection. Medical researchers exploring COVID-19 therapy have shown that trace elements play a significant role in maintaining immunity and treating viral infections. Among them, zinc and selenium may have favorable immune-modulatory properties (Jayawardena et al. 2020).

Zinc and selenium, which have antiviral and immunomodulatory capabilities, are components of antioxidant enzymes that can suppress virus reproduction in host cells and have a function in sustaining immunity and virus elimination (Pour et al. 2021). Low levels of zinc cause dysfunction in all immune cells, and altered zinc state have a higher risk for infection with COVID-19 (Wessels et al. 2020). The studies have also suggested a correlation between COVID-19 and selenium deficiency (Wessels et al. 2022).Therefore, we should pay attention to any variations in the trace element levels in the serum. In vitro, zinc can stop Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) from replicating and help with the immune response. Changes in hematological and immunological processes brought on by even a slight zinc deficit can result in pro-inflammatory phenotypes and redox metabolic diseases (Wessels et al. 2022). And a risk factor for persistent hypozincemia was identified as a severe case of COVID-19 (Yasui et al. 2020). Meanwhile, we learned from the clinical data that the COVID-19 patients showed a pronounced deficit in total serum selenium concentrations (Moghaddam et al. 2020). Therefore, we indicate these trace elements have such a function in the infection and severity of COVID-19.

This paper presented an extended series of discussion studies based on serum levels aimed at systematically assessing the relationship between micronutrients and the incidence of COVID-19 and its associated severity. We attempted to analyze the effect of microelements deficiency on the incidence of COVID-19 and its severity, to provide some basis for a subsequent randomized controlled trial.

Materials and methods

Search strategy

From database establishment to 9 February 2023, two researchers retrieved relevant peer-reviewed literature on zinc and selenium status in COVID-19 from PubMed, Embase, Web of Science and Cochrane databases. The search keywords included: (1) zinc; (2) selenium; (3) trace element; (4) corona virus OR COVID-19 OR Coronavirus Disease 2019 OR SARS-CoV2 OR SARS-CoV-2 OR 2019-nCoV. Searches were not restricted by language, study design, or country of origin. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). We also manually examined the references of the included publications for other relevant investigations. All studies were independently searched and evaluated by the two researchers. Disagreements were settled via consensus.

Inclusion and exclusion criteria

Studies were eligible for inclusion if the following criteria were all met: (1) evaluation of serum zinc or selenium or both; (2) participants were confirmed as COVID-19 patients and healthy human volunteers; (3) detailed prevalence or death information; (4) the number of patients ≥ 30; And exclusion criteria were: (1) case reports, reviews, conferences, meeting abstracts, meta-analyses, letters, comments; (2) data could not be extracted; Two investigators independently completed this process without language restriction, and any discrepancies were resolved by the third investigator.

Data extraction

We extracted the following data from the included studies: the first author, publish year, study design, demographic information of participants (age and gender), number of participants, type of trace element, serum levels in COVID-19 patients and healthy human volunteers, and serum levels in COVID-19 patients who have recovered and COVID-19 patients who have died, serum levels in mild and severe COVID-19 patients, and method for determination of trace elements. Data were tabulated independently by two researchers, and disagreements were resolved by negotiation.

Statistical analysis

All analyses were performed using Stata 16.0 (Stata Corporation, College Station, Texas, USA). In this analysis, zinc and selenium were calculated separately. And random effects models were used to calculate standardized mean differences (SMD) and the corresponding 95% confidence intervals (CI), which due to different data measurement methods or scales. If the original study provided median and interquartile intervals for serum micronutrient levels, we converted them to mean and standard deviation using validated formulas (Luo et al. 2018; Wan et al. 2014). Quality and risk of bias could be assessed through Newcastle–Ottawa Scale (NOS), funnel plots and Egger’s regression asymmetry test will be displayed if necessary.

Heterogeneity between pooled studies will be assessed using Cochrane Q and I2 statistics, with the values of I2 separated by 50%, representing low and high heterogeneity (McGuinness and Higgins 2020). Meta-regression analysis or sensitivity analysis will conduct to evaluate the probable group differences if existing considerable heterogeneity. Covariates will be based on severity of COVID-19 patients and referred to (1) number of patients included; (2) race; (3) study design.

Results

Literature search

Figure 1 showed the flow chart of literature retrieval. The electronic database search initially identified 5101 articles. Of these, 3115 studies were excluded as irrelevant after duplicating. The remaining 39 articles were carefully reviewed by full text to determine if they met the inclusion criteria and 19 articles were identified. Therefore, 2043 participants were evaluated for zinc and 1184 participants for selenium (Pour et al. 2021; Moghaddam et al. 2020; Shakeri et al. 2022; Ivanova et al. 2022; Zeng et al. 2021; Xu et al. 2022; Hosseini et al. 2021; Golabi et al. 2021; Elham et al. 2021; Voelkle et al. 2022; Al-Saleh et al. 2022; Skalny et al. 2021; Muhammad et al. 2021; Bego et al. 2022; Kocak et al. 2022; Almasaud et al. 2023; Younesian et al. 2022; Jahromi et al. 2021; Majeed et al. 2021; Laing et al. 2021). Details of the selected studies of zinc and selenium were summarized in Tables 1 and 2, respectively.

Fig. 1
figure 1

Flow diagram depicting the steps of database searching and research selection in accordance with the preferred reporting items for systematic reviews and meta analyses standards

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Table 1 Characteristics and outcomes of zinc in serum
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Table 2 Characteristics and outcomes of selenium in serum
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Association between Zinc/Selenium and severity in COVID-19.

This meta-analysis of 11 studies showed that an elevated serum zinc was associated with an increased risk of severe COVID-19 (SMD = 0.50, 95%CI 0.32–0.68, I2 = 50.5%, Fig. 2). The funnel-plot was qualitatively asymmetrical for zinc. Regression-based Egger’s test showed no indication of small-study effects for zinc (p = 0.784) on the severity of disease (Fig. 3). However, analysis of 8 studies that elevated selenium level was not associated with an increased risk of severe COVID-19 (SMD = − 0.03, 95%CI − 0.98–0.93, I2 = 96.7%).

Fig. 2
figure 2

Forest plot of severity of COVID-19 disease of zinc and selenium divided into two groups based on the microelement. The weighted risk difference for individual trails was represented by the center of each square, and the accompanying horizontal line indicated the 95 percent CI. The diamonds indicated the aggregated results. And two pictures were named with: Left. The increased risk of severe COVID-19 disease with zinc; Right. The increased risk of severe COVID-19 disease with selenium

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Fig. 3
figure 3

Funnel plot and Egger’s test on the severity of COVID-19 disease of zinc in the selected articles. And two pictures were named with: Above. Funnel plot with pseudo 95% confidence limits on zinc; Below. Egger’s test of zinc

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Association between Zinc/Selenium and mortality in COVID-19

This meta-analysis of 3 studies showed that null association between serum zinc level and mortality in COVID-19 (SMD = 1.66, 95% CI − 1.42–4.47). Similarly, the meta-analysis of three studies also found that null association between serum selenium level and mortality in COVID-19 (SMD = -0.16, 95% CI − 1.33–1.01, Fig. 4).

Fig. 4
figure 4

Forest plot of mortality in COVID-19 disease of zinc and selenium divide into two groups based on the microelement. The weighted risk difference for individual trials is represented by the center of each square, and the accompanying horizontal line indicates the 95 percent CI. The diamonds indicate the aggregated results. And two pictures were named with: Left. The mortality of COVID-19 disease with zinc; Right. The mortality of COVID-19 disease with selenium

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Association between Zinc/Selenium and risk of COVID-19 infection.

5 studied showed that serum zinc level was notable in COVID-19 patients (SMD = 1.21, 95% CI: 0.96–1.46, I2 = 54.3%). Similarly, three studies showed that serum selenium level was obvious in COVID-19 patients (SMD = 1.16, 95% CI: 0.71–1.61, I2 = 58.3%, Fig. 5).

Fig. 5
figure 5

Forest plot of risk in COVID-19 disease of zinc and selenium divide into two groups based on the microelement. The weighted risk difference for individual trials is represented by the center of each square, and the accompanying horizontal line indicates the 95 percent CI. The diamonds indicate the aggregated results. And two pictures were named with: Left. The risk of COVID-19 disease with zinc; Right. The risk of COVID-19 disease with selenium

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Discussion

Role of zinc and selenium and effect on the COVID-19.

In response to viral infections, zinc and selenium act in collaboration. By modifying the proteolytic process of replicating (Pour et al. 2021; Kieliszek and Lipinski 2020), RNA-dependent RNA polymerase, and lowering RNA synthesis activity in viral illnesses (Hosseini et al. 2021), zinc prohibits viruses from reproducing polyproteins. Additionally, the upregulation of alpha interferon (IFN-α) production in infected cells through janus kinase/signal transducer and activator of transcription 1 (JAK/STAT1) cells can limit the signaling pathway and its enhancement of antiviral activity under the control of zinc's regulation of antiviral immunity. Selenium, in this situation, is a crucial part of several enzymes. And along with vitamin E, selenium suppresses the creation of free radicals (Kieliszek and Lipinski 2020). Lack of selenium impairs immune system performance and speeds up virus multiplication and mutation (Xu et al. 2022; Keshavarzi et al. 2012). Natural killer (NK) cell activity and CD4+ T and B cell function are both improved by selenium (Golabi et al. 2021).

Golabi's investigations (Malavolta et al. 2015; Tanumihardjo et al. 2016) revealed a substantial negative association between serum zinc levels and illness severity in the context of the function of zinc in response to COVID-19, which is generally consistent with our findings. Additionally, SARS-CoV-2-infected cells accelerated the propagation of the virus in an in vitro experiment employing Vero E6 cells in the presence of serum zinc levels below 50 g/dl (Hosseini et al. 2021; Nouarie et al. 2004). Our findings were supported by the findings (Im et al. 2020; Derwand et al. 2020) that, regardless of how mild or severe their disease was, all COVID-19 patients displayed symptoms identical to hypozincemia, and that blood zinc levels in patients were 8% lower than those in the general population (Pourbagheri-Sigaroodi et al. 2020). One study (Hoang and Han 2020) demonstrated that the pre-onset zinc level and the hypoglycemic response during infection are what determine the serum zinc ion concentration in patients infected with the virus. This finding correlates with the prevalence of SARS-CoV-2 affected by zinc deficiency in our study. According to other research (Moghaddam et al. 2020; Laing et al. 2021; Shang et al. 2020), zinc might somewhat decrease the SARS-CoV-2 virus's ability to replicate and, as a result, its viral activity. This finding raises the possibility that zinc, in conjunction with existing medications, could be used as a treatment for COVID-19 patients. Moreover, in a randomized controlled trial by Patel et al. (2021), high doses of intravenous zinc reversed the symptoms of zinc deficiency in the acute phase of COVID-19. This provided a deeper implication. However, in other clinical trials (Patel et al. 2021; Abd-Elsalam et al. 2021; Thomas et al. 2021), the positive effect of zinc supplement and its ion carrier hydroxychloroquine on COVID-19 patients was weak or almost lost its effect. This led to the prevention and repair role of zinc in COVID-19 patients unclear.

Metabolism of selenium and selenoproteins may improve the outcome of SARS-CoV-2 infection by reducing virus-induced oxidative stress, excessive inflammatory response and immune system dysfunction (Zhang et al. 2020a). There was a correlation between serum selenium status and COVID-19 cure rates (Shakeri et al. 2022; Wintergerst et al. 2006), particularly in individuals with inadequate or low selenium intakes (Al-Saleh et al. 2022). More than that, one study (Gammoh and Rink 2017) has revealed a significant frequency of thrombotic problems in patients with COVID-19 disease. Selenium regulates the production of pro-inflammatory components of thromboxane A2 (TXA2) and lipoxygenase, which in turn affects the arachidonic acid pathway. Furthermore, selenium status was positively associated with survival in patients infected with COVID-19 compared to patients not infected with COVID-19 (Kieliszek 2023). Moreover, selenium levels have reduced in COVID-19 patients worldwide (Zhang et al. 2020b; Rataan et al. 2022), suggesting a relationship between selenium deficiency and COVID-19 infection. Additionally, low C-reactive protein (CRP), neutrophil count to neutrophil to lymphocyte ratio (NLR), and lymphocyte and monocyte ratio (LMR) were associated with elevated selenium levels (Younesian et al. 2022; Schroeder and Cousins 1990; Shamblott et al. 1998), implying that selenium has an anti-inflammatory effect, particularly during viral infections, and also implying a positive correlation between selenium deficiency and the incidence of COVID-19 relationship. However, when modifying models for certain inflammatory indicators, these correlations were favorably changed (Carlucci et al. 2020; Skalny et al. 2020), indicating that selenium is independently linked with COVID-19 disease severity. Furthermore, the association of excess selenium intake with cure rates for COVID-19 has been demonstrated, although selenium intake to toxic levels is not recommended for selenium-sufficient individuals (Rayman 2012).

Heterogeneity and limitations

Utilizing a subgroup analysis to reduce the heterogeneity, we performed meta regression with disease extent (healthy vs patient; recovered vs dead; non-severe vs severe) as the subject compared with others and obtained relevant images. We considered that Pour's article might be a source of heterogeneity in our article, possibly due to the different inclusion measures of the data or to the intake of micronutrient supplements by the patients (Gouda et al. 2021; Hoffmann and Berry 2008), although he was consistent in terms of zinc. To obtain more precise results, we performed a sensitivity analysis involving selenium. It found that the removal of Pour’s article changed from SMD ( 0.03, 95% CI:  0.98–0.93) to SMD (0.36, 95% CI: 0.04–0.68) in terms of the severity of selenium and COVID-19, and started to show a positive correlation (Fig. 6), which coincided with the findings of Gombart et al. (2020). In addition, after we adopted NOS, each article scored above 5, which classified as high-quality articles.

Fig. 6
figure 6

Forest plot of severity of COVID-19 disease of selenium compared between two groups. And two pictures were named with: Left. The increased risk of severe COVID-19 disease with selenium; Right. The increased risk of severe COVID-19 disease with selenium with one research removing

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At limitations, this article was limited by the amount of available literature and the way in which it was investigated, among others. Moreover, based on the current studies, very few studies were available to confirm the therapeutic effect of zinc. In the case of selenium, few articles were enough to demonstrate its clinical efficacy. Although we tried to analyze the effects of two serum micronutrient deficiencies on COVID-19, the possible role of these micronutrients for the organism remained more controversial (Balboni et al. 2022). This was possibly because the influence of the subject's own nutritional status, environmental and age factors can be equally limiting conditions when supplementing and testing for these two elements. Therefore, preventive or therapeutic interventions targeting COVID-19 based on zinc or selenium supplementation were currently not justified.

Conclusion

The meta-analysis showed that the correlation between zinc and selenium deficiency and the degree of risk for COVID-19 held, and zinc deficiency showed a higher correlation with the degree of progression of COVID-19. Nevertheless, due to the lack of randomized controlled trials, our conclusions need to be confirmed by randomized controlled trials with larger numbers of subjects.