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Ezzati, A.;  Rosenkranz, S.K.;  Horne, B.D. Dietary Supplements on Inflammatory Markers and SARS-CoV-2 Infection. Encyclopedia. Available online: https://encyclopedia.pub/entry/31669 (accessed on 02 July 2024).
Ezzati A,  Rosenkranz SK,  Horne BD. Dietary Supplements on Inflammatory Markers and SARS-CoV-2 Infection. Encyclopedia. Available at: https://encyclopedia.pub/entry/31669. Accessed July 02, 2024.
Ezzati, Armin, Sara K. Rosenkranz, Benjamin D. Horne. "Dietary Supplements on Inflammatory Markers and SARS-CoV-2 Infection" Encyclopedia, https://encyclopedia.pub/entry/31669 (accessed July 02, 2024).
Ezzati, A.,  Rosenkranz, S.K., & Horne, B.D. (2022, October 27). Dietary Supplements on Inflammatory Markers and SARS-CoV-2 Infection. In Encyclopedia. https://encyclopedia.pub/entry/31669
Ezzati, Armin, et al. "Dietary Supplements on Inflammatory Markers and SARS-CoV-2 Infection." Encyclopedia. Web. 27 October, 2022.
Dietary Supplements on Inflammatory Markers and SARS-CoV-2 Infection
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This entry is adapted from the peer-reviewed paper 10.3390/nu14204299

A key characteristic of severe presentations of acute SARS-CoV-2 infection involves overactive host inflammatory responses, with a substantial proportion of severe outcomes such as hospitalizations and deaths from COVID-19 linked to hyper-inflammation. Inflammation and oxidative stress play pivotal roles in the progression of infectious diseases including COVID-19. Evidence suggests that high sensitivity (hs) C-reactive protein (CRP), interleukin (IL)-6, and matrix metalloproteinases (MMPs) are among the most important biomarkers of COVID-19 severity, similar to the chronic conditions involved in vascular aging. Lactate dehydrogenase (LDH) and hsCRP are also biomarkers of respiratory failure in patients with COVID-19. Furthermore, it is well established that elevated levels of other inflammatory markers are common in COVID-19 patients. These markers include IL-1β, IL-7, IL-8, IL-18, interferon (IFN)-γ, tumor necrosis factor (TNF)-α, procalcitonin (PCT), serum ferritin, and erythrocyte sedimentation rate (ESR).

SARS-CoV-2 dietary supplements COVID-19 inflammation vitamin D probiotics quercetin

1. Vitamins and Minerals

Supplementation with vitamins such as A, B, C, D, and E is thought to play a significant role in the severity of COVID-19 infection by reducing inflammation, time to recovery, and preventing lung fibrosis [1][2]. To authors' knowledge, no RCTs have tested the effects of supplementation with vitamin A, B, or C alone, on COVID-19 severity; however, in a 7-day randomized placebo-controlled trial of 60 COVID-19 patients admitted to intensive care unit (ICU), those who received a combination of vitamins A (25,000 IU daily), D (600,000 IU; one dose), E (300 IU twice daily), C (500 mg four times daily), and a B-complex ampule (daily), demonstrated significant reductions in the duration of hospitalization, TNF-α, Il-6, erythrocyte sedimentation and hs-CRP, but not IFN-γ, as compared to a placebo [3]. In contrast, 10-days of standard treatment plus high doses of vitamin C (2 g), Melatonin (6 mg), and Zinc (50 mg), was not effective for lowering inflammatory markers or length of hospitalization in 20 patients with severe COVID-19 [4].
Accumulating data highlight the immunomodulatory role of vitamin D, and link hypovitaminosis D (25 OHD ≤ 20 ng/mL) with hyperinflammation (i.e., the so-called “cytokine storm”) and elevated risk of mortality in patients with COVID-19 [5][6][7][8]. Therefore, supplementation with vitamin D is suggested to attenuate the risk of the cytokine storm, and the severity of COVID-19 [5][9]. The impact of vitamin D on inflammatory markers and in response to SARS-CoV-2 infection has been explored in several RCTs (see Table 1). The current state of evidence from RCTs indicates that higher doses of daily intake of vitamin D can reduce the levels of inflammatory markers like IL-6, hsCRP, and time to recovery in COVID-19 patients [10][11]. Ten days of supplementation with 60,000 IU/day of vitamin D in combination with standard treatment significantly reduced IL-6, hsCRP, LDH, ferritin, and Neutrophil/Lymphocyte ratio, in 87 hospitalized COVID-19 patients with vitamin D deficiency (D < 30 ng/m) as compared with the controls, who received standard treatment for 8 to 10 days [11]. Similarly, in a 2-week trial, oral intakes of two different doses of vitamin D3 (5000 IU vs. 1000 IU) resulted in significant decreases in plasma IL-6 versus baseline, with no between group differences, while hsCRP levels remained unchanged in both groups [10]. Furthermore, time required for resolving cough symptoms with D3 supplementation (5000 IU) was significantly shorter compared to the comparison group [10]. Rastogi et al. investigated the effects of high-dose vitamin D supplementation (60,000 IU) as compared with control in 40 SARS-CoV-2 RNA positive individuals. Patients with vitamin D deficiency (25(OH) D < 20 ng/mL) who were positive for SARS-CoV-2 RNA, with mild or no symptoms, significantly improved with regard to viral SARS-CoV-2 RNA clearance (62.5% vs. 20.8%) and fibrinogen levels [12]. In contrast, a single dose of vitamin D was ineffective for lowering inflammatory markers and for the treatment of patients with severe COVID-19 [13][14][15].
Evidence for the potential role of zinc supplementation for COVID-19 infection is inconclusive [16][17][18]; with only one 28-day RCT of 191 patients with COVID-19 having investigated the effects of zinc supplementation (50 mg of zinc twice daily) combined with chloroquine/hydroxychloroquine (CQ/HCQ) on inflammatory markers. The study results indicated no significant changes in hs-CRP levels or clinical recovery time [19].
Table 1. Summary of Randomized controlled trials (RCTs) on the impact of dietary supplements on inflammatory markers and in response to SARS-CoV-2.
Authors/Year/Country Duration Participants Study Design TNF-α IL-1β IL-4 IL-6 IL-10 CRP IFN-γ Other Outcomes
Rastogi et al., 2020 [12]
India		 7-d 40 SARS-CoV-2 RNA positive individuals RCT:
1.Daily oral cholecalciferol (60,000 IU) with therapeutic target 25(OH)D > 50 ng/mL
2. Control		 - - - - - Ø - ↓ † Fibrinogen
↑ † Negative conversion of SARS-CoV-2 RNA (62.5% vs. 20.8%)
Murai et al., 2021 [15]
Brazil		 - 237 patients
hospitalized for moderate to severe COVID-19		 RCT:
1.A single oral dose of 200,000 IU of vit. D3
2. Placebo		 - - - - - Ø - Ø
Same LOS (median of 7.0 vs. 7.0 days)
Lakkireddy et al., 2021 [11]
India		 8–10-d 87 Patients hospitalized for COVID-19
Vit. D  <  30 ng/m		 RCT:
1. 60,000 IU/day of oral vitamin D +standard treatment
2. Only standard treatment		 - - - 1. ↓ †
2. Ø		   1. ↓ *†
2. ↓ *		 - ↓ *† LDH, ferritin, N/L ratio
Beigmohammadi et al., 2021 [3] Iran 7-d 60 ICU-admitted COVID-19 patients RCT:
1. Oral Vit. A (25,000 IU) daily, vit.D (600,000 IU; one dose), vit. E (300 IU twice daily), vit. C (500 mg four times daily), and one amp daily of B complex
2. Placebo		 1. ↓ *†
2. ↓ *		 - - 1. ↓ *†
2. ↓ *		 - 1. ↓ *†
2. ↓ *		 1. ↓ *
2. ↓ *		 ↓ † Hospitalization rate and ESR in treatment group
Sabico et al., 2021 [10]
Saudi Arabia		 14-d 69 patients COVID-19 and sub-optimal vit. D status RCT:
1.Oral vit. D3 (5000 IU)
2.Oral vit. D3 (1000 IU)		 - - - 1. ↓ *
2. ↓ *
-		 1. Ø
2. Ø		 - ↓ † Time to recovery in resolving cough with D3 (5000 IU) vs. D3 (1000 IU)
Abd-Elsalam
et al., 2021 [19] Egypt		 4 weeks 191 patients with COVID-19 RCT:
1.CQ/HCQ + 220 mg of zinc sulfate twice daily
2. HCQ only		 - - - - - Ø - Ø Clinical efficacy of HCQ
Di Pierro et al., 2021 [20]
Italy		 2 weeks 42 COVID-19 outpatients RCT:
1. Quercetin (500 mg/day (first week) and of 1000 mg/day (second week)
2. Standard of care		 - - - - - Ø - ↓ † LOS, virus clearance, symptoms frequency, LDH, ferritin
Doae et al., 2021 [21]
Iran		 2 weeks 128 critically ill COVID-19 patients RCT:
1. 1000 mg omega-3 daily (400 mg EPAs and 200 mg DHAs)
2. Control		 - - - - - - - ↑ † 1-month survival rate, pH, HCO3, and Be
↓ † Levels of BUN, Cr, and K in the treatment group
Darban et al., 2021 [4]
Iran		 10-d 20 patients with severe COVID-19 Pilot RCT:
1. Standard
care + oral zinc sulfate (220 mg containing 50 mg zinc)
, oral melatonin (6
mg, q6hr), and intravenous vit. C (2 g)
2. Standard care alone		 - - - - - 1. ↓ *
2. ↓ *		 - Ø LOS
Sedighian et al., 2021 [22]
Iran		 2 weeks 30 patients with COVID-19 Single blind RCT:
1. Hydroxychloroquine + 2 g DHAs and EPAs
2. Hydroxychloroquine		 - - - - - 1. ↓ † - † Body pain and fatigue in the treatment group
Ø Olfactory
Cannata-Andía et al., 2022 [14] Spain - 543 patients with moderate to severe COVID-19 RCT:
1. A single-oral bolus of 100,000 IU of cholecalciferol
2. Control		 - - - Ø - Ø - Ø Hospitalization rate and death
Shohan et al., 2022 [23]
Iran		 7-d 60 patients with severe COVID-19 RCT:
1. Quercetin (1000 mg daily) + antiviral drugs
2. Antiviral drugs		 ↓ * ↓ * - ↓ † - ↓ † - ↓ † ALP, LDH
Ø Mortality, duration of ICU-admission
Pimentel et al., 2022 [24]
Brazil		 7-d 43 adult patients with COVID-19 RCT:
1. Two 200 mL units of high-protein nutritional supplement (arginine, omega-3 fatty acids and nucleotides) over 24 h
2. Two 200 mL units of high-protein nutritional supplement alone		 - - - - - 1. ↓ †
2. Ø

-		 ↑ Lymphocytes in the treatment group
↓ Lymphocytes in the control group
Fernandes et al., 2022 [13]
Brazil		 - 200 patients with moderate to severe COVID-19 RCT:
1. Single oral dose of vit. D3 (200 000 IU)
2. Placebo		 Ø Ø Ø Ø Ø - Ø -
Gutiérrez-Castrellón et al., 2022 [25]
Spain		 30-d 293 COVID-19 outpatients RCT:
1. Probiotic (Lactiplantibacillus plantarum stains KABP022, KABP023 and KABP033 = Pediococcus acidilactici strain KABP021)
2. Placebo		 - - - - - 1. ↓ †
hs-CRP
Only on day 15		 - ↓ † Complete remission (53.1% in probiotic group vs. 28.1% in placebo; p < 0.001)

-: Not measured. Ø: Non-significant difference between groups. * p < 0.05, Significantly different from baseline (within group effect). † p < 0.05, Significantly different from the control or. comparison group. TNF-α: tumor necrosis factor -α; IL-1β: Interleukin-1β; IL-4: Interleukin-4; IL-6:Interleukin-6; IL-10: Interleukin-10; IFN-γ: Interferon gamma; CQ/HCQ:Chloroquine/hydroxychloroquine; HCQ: Hydroxychloroquine; ALP: Alkaline phosphatase; Lactate dehydrogenase; Be: Base excess; BUN: Blood urea nitrogen; Cr: creatinine; LOS: Length of hospital stay; LDH: Lactate dehydrogenase; N/L ratio: Neutrophil/Lymphocyte ratio; ESR: Erythrocyte sedimentation rate; DHA: Docosahexaenoic acid; EPA: eicosapentaenoic acid.

2. n-3 Polyunsaturated Fatty Acids (PUFAs)

It is well known that n-3 PUFAs including eicosatetraenoic acid (EPA) and docosahexaenoic acid (DHA) have anti-inflammatory properties [26][27][28]. The current state of evidence from RCTs suggests that supplementation with n-3 fatty acids appears to be effective for alleviating clinical symptoms and inflammatory responses in patients with COVID-19 (see Table 1). Three of the trials included herein investigated the efficacy of n-3 PUFAs for COVID-19 outcomes [21][22][24]. Supplementation with daily omega-3 capsules (1000 mg; 400 mg EPAs and 200 mg DHAs) for 2 weeks resulted in significantly higher 1-month survival rates in 128 ICU patients with COVID-19 when compared to the control patients [21]. The study also reported meaningful improvements in respiratory and renal function parameters such as arterial PH, bicarbonate, and other base excess in the treatment group. Similarly, DHA and EPA supplementation (2 g) plus hydroxychloroquine, significantly reduced hs-CRP, body pain, and fatigue compared to hydroxychloroquine alone in 30 patients with COVID-19 [22]. In agreement with those results, a 7-day trial in 43 patients with COVID-19 who were treated with oral immuno-nutrient supplements containing arginine, omega-3 fatty acids, and nucleotides (Two 200 mL units over 24 h), indicated meaningful reductions in hs-CRP when compared with the patients who were given only high-protein nutritional supplements (Two 200 mL units) [24].

3. Quercetin

Quercetin—a polyphenol with antioxidant and anti-inflammatory properties—is widely known to have favorable effects on inflammation and infection [29][30][31]. Di Pierro et al. reported that in 42 outpatients with COVID-19, two weeks of quercetin therapy (500–1000 mg daily) significantly diminished the rate (−68.2%) and length (−76.8%) of hospitalization, the need for non-invasive oxygen therapy (−93.3%), and the mortality rate (although events were very limited: none vs. 3 people) compared to the control (standard of care) [20]. Furthermore, significant reductions in LDH and ferritin levels were reported in the treatment group vs. control, while hs-CRP remained unchanged [20]. Unlike the 2-week trial by Di Pierro et al., a shorter 7-day RCT including 60 patients with severe COVID-19, treated with daily quercetin (1000 mg) along with antiviral drugs, compared with control (only antiviral drugs), did not alter mortality or ICU-admission duration significantly. Notably, significant reductions in inflammatory markers such as TNF-α, IL-1β, IL-6, hs-CRP, ALP, and LDH were shown in the treatment group as compared to the control or baseline [23].

4. Probiotics

High quality evidence from systematic reviews and meta-analyses of RCTs, indicates that probiotics may have a favorable role for responses to infections [32]. In a recent one-month RCT of 293 outpatients with COVID-19, supplementation with four-strain probiotics consisting of Lactiplantibacillus plantarum KABP033 (CECT30292), L. plantarum KABP022 (CECT7484), L. plantarum KABP023 (CECT7485), and Pediococcus acidilactici KABP021 (CECT7483), produced significant reductions in remission rates vs. placebo (53.1% in probiotic group vs. 28.1% in placebo [25].

References

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Subjects: Nutrition & Dietetics
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Armin Ezzati
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Sara K. Rosenkranz
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Benjamin D. Horne
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Update Date: 28 Oct 2022
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