Essential metals, vitamins and antioxidant enzyme activities in COVID-19 patients and their potential associations with the disease severity

Abstract

The role of micronutrient deficiency in the pathogenesis of COVID-19 has been reviewed in the literature; however, the data are limited and conflicting. This study investigated the association between the status of essential metals, vitamins, and antioxidant enzyme activities in COVID-19 patients and disease severity. We recruited 155 patients, who were grouped into four classes based on the Adults guideline for the Management of Coronavirus Disease 2019 at King Faisal Specialist & Research Centre (KFSH&RC): asymptomatic (N = 16), mild (N = 49), moderate (N = 68), and severe (N = 22). We measured serum levels of copper (Cu), zinc (Zn), selenium (Se), vitamin D 3 , vitamin A, vitamin E, total antioxidant capacity, and superoxide dismutase (SOD). Among the patients, 30%, 25%, 37%, and 68% were deficient in Se (\ 70.08 lg/L), Zn (\ 0.693 lg/mL), vitamin A (\ 0.343 lg/mL), and vitamin D 3 (\ 20.05 lg/L), respectively, and SOD activity was low. Among the patients, 28% had elevated Cu levels ([ 1.401 lg/mL, KFSH&RC upper reference limit). Multiple regression analysis revealed an 18% decrease in Se levels in patients with severe symptoms, which increased to 30% after adjusting the model for inflammatory markers. Regardless of inflammation, Se was independently associated with COVID-19 severity. In contrast, a 50% increase in Cu levels was associated with disease severity only after adjusting for C-reactive protein, reflecting its possible inflammatory and pro-oxidant role in COVID-19 pathogenesis. We noted an imbalance in the ratio between Cu and Zn, with * 83% of

Immunomodulatory Role of Microelements in COVID-19 Outcome: a Relationship with Nutritional Status

“…COVID-19 patients had significantly lower Zn levels in comparison to the healthy controls: median 74.5 µg/dl ( IQR 53.4–94.6 µg/dl) versus 105.8 µg/dl ( IQR 95.65–120.90 µg/dl), p < 0.001) COVID-19 patients with ZN deficiency had a higher risk for developing complications ( OR 5.54, IC del 95%: 1.56–19.6, p = 0.008) and for mortality ( OR 5.48, 95% CI 0.61–49.35, p = 0.129) Zeng, et al 2021 [ 89 ] China 306 hospitalized COVID-19 patients -Severe cases ( n = 104, 34.0%) -Non‐severe cases ( n = 202, 66.0%) Retrospective cohort study Non-severe cases had higher Zn levels 6.61 (5.91–7.25) µg/L than severe cases 6.18 (5.67–6.79) µg/L, p < 0.001 Reference Zn normal levels: 4.3–7.8 mg/L A correlation between Zn and magnesium levels ( CC 0.36 p < 0.05), as well as Zn and iron ( CC 0.64 p < 0.05), was detected, suggesting a possible synergic effect in COVID-19 Kocak, et al 2021 [ 77 ] Turkey 92 adults -SARS-CoV-2 infected ( n = 60) -Healthy ( n = 32) Observational study Zn serum levels in COVID-19 patients were lower (588.17 ± 195.02 ppb) than those of healthy participants (873.4 ± 335.38 ppb, p < 0.001) A gradual decrease between Zn levels and severity were detected when assigning COVID-19 patients into groups of mild, moderate, and severe disease manifestations ( p < 0.0001) Al-Saleh, et al 2022 [ 53 ] Saudi Arabia 155 COVID-19 patients 18–95 years old -Asymptomatic ( n = 16) -Mild ( n = 49) -Moderate ( n = 68) -Severe ( n = 22) Cross-sectional observational study Low levels of Zn in 25% of patients (Zn deficiency: < 0.693 µg/mL) No association between Zn levels and severity, vitamin E, and vitamin D3 serum levels was detected, after adjusting for inflammatory markers and laboratory parameters Cooper Hackler, et al 2021 [ 103 ] Germany 35 hospitalized COVID-19 patients 173 consecutive serum samples High levels of Cu were associated with survival (Cu; 1475.9 ± 22.7 µg/L vs. 1317.9 ± 43.9 µg/L; p < 0.001), ...…”

“…Serum Se levels were significantly lower in deceased COVID-19 patients vs. survivors (40.8 ± 8.1 µg/L vs. 53.3 ± 16.2, p < 0.001) A total of 39.6% of COVID-19 patient samples were deficient in SELENOP (normal levels 2.56–6.63 mg/L) Serum Se and SELENOP showed the expected strong correlation ( r = 0.7758, p < 0.001) A total of 64.7% of deceased COVID-19 patients were Se deficient and 70.6% were SELENOP deficient while 39.3% and 32.6% of surviving patients were Se and SELENOP deficient, respectively Kocak, et al 2021 [ 77 ] Turkey 92 adults -SARS-CoV-2 infected ( n = 60) -Healthy ( n = 32) Observational study Serum Se levels were significantly lower in SARS-Co V - 2 infected patients when compared with healthy adults (255.23 ± 42.67 ppb vs 255.23 ± 42.67 ppb, respectively Patients with mild, moderate, and severe disease had significantly lower selenium levels than healthy, asymptomatic patients ( p < 0.001), suggesting that serum Se level is important in asymptomatic treatment of the disease Razeghi, et al 2021 [ 3 ] Iran 84 COVID-19 patients -Mild ( n = 38) -Moderate ( n = 27) -Severe ( n = 19) Observational study Serum Se was as follows: 47.07 ± 20.82 ng/mL, 47.36 ± 25.6 ng/mL, 29.86 ± 11.48 ng/mL in the mild, moderate, and severe disease group, respectively Significant negative association between serum Se level and COVID-19 severity (standardized coefficient = − 0.28, p = 0.01) Al-Saleh, et al 2022 [ 53 ] Saudi Arabia 155 COVID-19 patients 18–95 years old -Asymptomatic ( n = 16) -Mild ( n = 49) -Moderate ( n = 68) -Severe ( n = 22) Cross-sectional observational study Thirty percent of total participants were deficient in Se (< 70.08 µg/L) Patients with severe symptoms were Se deficient in 18% of the cases Se was independently associated with COVID-19 severity ( p = 0.214) Zinc Jothimani, et al 2020 [ 88 ] India 47 COVID-19 patients 45 healthy controls Prospective study Low zinc levels in 57.4% of COVID-19 patients (normal reference levels: 71.8–79.6 µg/dl). COVID-19 patients had significan...…”

“…Patients with serum Vit A < 0.2 mg/L were significantly associated with the development of acute respiratory distress syndrome ( OR = 5.54 [1.01–30.26]; p = 0.048), mortality ( OR 5.21 CI 1.06–25.5, p = 0.042), and inflammatory markers, such as c-reactive protein, ferritin, albumin, and lymphocyte count ( p < 0.001) Tomasa—Irriguible et al 2021 [ 5 ] Spain 120 hospitalized COVID-19 patients, with acute respiratory distress syndrome criteria Cross-sectional descriptive study Low levels of Vit A in 71.7% of patients, with a mean value of 0.17 ± 0.06 mg/L (normal levels > 0.3 mg/L). Vit A deficiency was associated with male sex (69% vs. 45%, p = 0.02), with the need for ICU admission (62.1% vs. 20.7%; p = 0.048), the orotracheal intubation rate (92.3% vs. 7.7%; p = 0.000), the need for prone position (93.6% vs. 6.4%; p = 0.0001), the need for norepinephrine (92.9% vs. 7.1%; p = 0.001), and a higher rate of respiratory bacterial superinfection (92.6% vs. 7.4%; p = 0.016) Al-Saleh et al 2022 [ 53 ] Saudi Arabia 155 COVID-19 patients 18–95 years old -Asymptomatic ( n = 16) -Mild ( n = 49) -Moderate ( n = 68) -Severe ( n = 22) Cross-sectional descriptive study Low levels of Vit A in 36.5% of patients (normal levels > 0.34 µg/mL) A 23% decrease in Vit A in patients with severe symptoms, which disappeared after adjusting for inflammatory markers Vitamin B Itelman et al 2020 [ 58 ] Israel 162 COVID-19 patients 52 ± 20 years old -Mild ( n = 92) -Moderate ( n = 44) -Severe ( n = 26) Cohort study Folic acid levels were significantly lower in severe patients when compared with moderate and mild cases (9.6 ng/mL vs. 12.9 ng/mL vs. 18.2 ng/mL, p = 0.005) A total of 80.8% of patients with severe COVID-19 were admitted to the intensive care unit ( p = < 0.001). All deaths were in the severe disease subgroup (19.2%) Deschasaux—Tanguy et al 2021 [ 57 ] France 7766 adults -311 positive for anti-SARS-CoV-2 antibodies NutriNet-Santé web-based cohort study SARS-CoV-2 negative participants had a higher intake of Vit B9 when compared with positive patients (330 ± 90 µg/day and 3...…”

“…Dietary intake of Vit B9 ( OR = 0.84 CI 0.72, 0.98, p = 0.02) was associated with a decreased probability of SARS-CoV-2 infection Tan et al 2020 [ 59 ] Singapore 43 hospitalized COVID-19 patients > 50 years old -Intervention group: Vitamin B12, D, and Mg supplementation ( n = 17) -Control group ( n = 23) Cohort observational study Patients with Vit B12, D, and Mg supplementation had a lower need to start oxygen therapy ( OR 0.13, 95% CI 0.03–0.59) and intensive care support ( OR 0.20 95% CI 0.04–0.93) than the control group, during their hospital stay Vitamin D Rodriguez et al 2020 [ 68 ] Mexico 172 COVID-19 patients 51.44 ± 14 years old Cross-sectional observational study Vit D deficiency in 68% of patients No significant differences were found between mortality and Vit D levels (deceased 13.6 ± 6.36 ng/mL vs. survivors 17.30 ± 7.44 ng/mL, p = 0.25). Patients with Vit D < 8 ng/mL have a 3.69-fold risk of dying compared to those with levels > 8 ng/mL ( OR 3.69, CI 1.62–8.37, p = 0.001) Kaufman et al 2020 [ 66 ] USA 191,779 patients who underwent SARS-CoV-2 testing, who had Vit D testing results from the previous 12 months Retrospective, observational study Patients with deficiency (< 20 ng/mL) of Vit D ( n = 39,190) had a higher positivity rate for SARS-CoV-2 than those with adequate (30–34 ng/mL) Vit D levels (12.5%, CI , 12.2–12.8% vs. 8.1%, CI 7.8–8.4%) SARS-CoV-2 positivity was strongly and inversely associated with circulating Vit D ( R 2 = 0.96), a relationship that persists across latitudes, races/ethnicities, both sexes, and age ranges Hastie et al 2021 [ 67 ] UK 341,484 UK Biobank participants -203 died due to COVID-19 Retrospective, observational study Vit D serum concentration was associated with severe COVID-19 infection and mortality ( HR 0.92; 95% CI 0.86–0.98; p = 0.016), but not after adjustment for confounders ( HR 0.98; 95% CI 0.91–1.06; p = 0.696) Al-Saleh et al 2022 [ 53 ] …”

“…Patients with Vit D < 8 ng/mL have a 3.69-fold risk of dying compared to those with levels > 8 ng/mL ( OR 3.69, CI 1.62–8.37, p = 0.001) Kaufman et al 2020 [ 66 ] USA 191,779 patients who underwent SARS-CoV-2 testing, who had Vit D testing results from the previous 12 months Retrospective, observational study Patients with deficiency (< 20 ng/mL) of Vit D ( n = 39,190) had a higher positivity rate for SARS-CoV-2 than those with adequate (30–34 ng/mL) Vit D levels (12.5%, CI , 12.2–12.8% vs. 8.1%, CI 7.8–8.4%) SARS-CoV-2 positivity was strongly and inversely associated with circulating Vit D ( R 2 = 0.96), a relationship that persists across latitudes, races/ethnicities, both sexes, and age ranges Hastie et al 2021 [ 67 ] UK 341,484 UK Biobank participants -203 died due to COVID-19 Retrospective, observational study Vit D serum concentration was associated with severe COVID-19 infection and mortality ( HR 0.92; 95% CI 0.86–0.98; p = 0.016), but not after adjustment for confounders ( HR 0.98; 95% CI 0.91–1.06; p = 0.696) Al-Saleh et al 2022 [ 53 ] Saudi Arabia 155 COVID-19 patients 18–95 years old -Asymptomatic ( n = 16) -Mild ( n = 49) -Moderate ( n = 68) -Severe ( n = 22) Cross-sectional observational study Low levels of Vit D3 in 68% of patients (normal levels > 20.05 µg/mL) Twelve of sixteen deceased patients had Vit D3 levels < 12 µg/mL (mean 5.09 µg/mL), but without differences with Vit D3 levels in survivors (4.81 µg/mL) No association between vit D3 levels and severity, total antioxidant capacity, or superoxide dismutase was detected, after adjusting for inflammatory markers and laboratory parameters Selenium Moghaddam, et al 2020 [ 41 ] Germany 33 COVID-19 patients 166 consecutive serum samples Cross-sectional observational study A total of 44.4% of COVID-19 patient samples were Se deficient (normal levels 45.7–131.6 µg/L). Serum Se levels were significantly lower in deceased COVID-19 patients vs. survivors (40.8 ± 8.1 µg/L vs. 53.3 ± 16.2, p < 0.001) A total of 39.6% of COVID-19 patient samples were deficient in SELENOP (normal levels 2.56–6.63 mg/L) Serum Se and SELENOP showed the expected stro...…”