Table 1.
Summary of clinical studies findings regarding respiratory viral infections and COVID-19 in association with microelement concentrations
| Authors, year | Country | Participants/study type | Outcomes | |
|---|---|---|---|---|
| Vitamin A | Zhang et al. 2020 [50] | China |
277,064 children 0–14 years old Cross-sectional study |
Subclinical Vit A deficiency (serum Vit A < 0.2 mg/L) prevalence of 10.4% Children with recurrent respiratory infections were more vulnerable to subclinical Vit A deficiency (21.3%, 95% CI: 20.5–22.2%) |
| Tepasse et al. 2021 [51] | Germany |
40 COVID-19 hospitalized patients: -Moderate (n = 9): 54 (30–81) years old -Severe (n = 9): 50 (39–73) years old -Critical (n = 22): 58 (41–82) years old 47 age-matched convalescent persons (control group): 54 (41–70) years old Prospective, multicenter observational cross-sectional study |
Gradual association between low Vit A levels and greater severity of COVID-19. 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 320 ± 90 µg/day, respectively, p = 0.004). 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 (R2 = 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 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-CoV-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 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), the same way its biomarker, ceruloplasmin (CP; 547.2 ± 19.5 mg/L vs. 438.8 ± 32.9 mg/L, p = 0.086) A positive linear correlation between Cu and Se levels was detected in COVID-19 patients, but not consistent during the acute phase response (R = 0.23, p = 0.003) |
| 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 |
Higher Cu levels in severe COVID-19 patients (929.73, 828.52–1080.02 µg/L) than in non-severe cases (838.55, 770.47–950.13 µg/L) Cu reference normal levels: 634.1–999.4 µg/L |
|
| Kocak, et al. 2021 [77] | Turkey |
92 adults -SARS-CoV-2 infected (n = 60) -Healthy (n = 32) Observational study |
No significant difference between COVID-19 patients Cu serum levels (952.48 ± 388.75 ppb) and healthy participants (2795.99 ± 9605.09 ppb) was detected, p > 0.05 The Zn/Cu ratio in COVID-19 patients (median ± SD, 0.68 ± 0.28) vs healthy patients (median ± SD, 0.86 ± 0.63) was not significant. However, the Zn/Cu ratio showed a significant positive correlation with hemoglobin |
|
| 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 Cu in 3.2% of patients. Cu reference levels: 1 < 0.701 µg/mL Asymptomatic (1.30 ± 0.678 µg/mL), mild (1.31 ± 0.351 µg/mL), moderate (1.25 ± 0.341 µg/mL), and severe (1.22 ± 0.370 µg/mL) Eighty-three percent of patients having a Cu/Zn ratio > 1. This ratio is associated with COVID-19 severity when adjusted for inflammatory marker parameters (p < 0.05) |
Vit A, vitamin A; mg/L, milligrams per liter; CI, confidence interval; OR, odds ratio; COVID-19, coronavirus disease 2019; SARS-CoV-2, respiratory syndrome coronavirus 2; ICU, intensive care unit; µg/mL, micrograms per milliliter; ng/mL, nanograms per milliliter; µg/day, micrograms per day; µg/L, micrograms per liter; Vit B9, vitamin B9; Vit B12, vitamin B12; Vit D, vitamina D; Mg, magnesium; Vit B3, vitamin B3; HR, hazard ratio; SELENOP, selenoprotein P; ppb, parts per billion; Cu, cooper; Se, selenium; Zn, zinc; CP, ceruloplasmin