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 [39,40]. To our 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 [41]. 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 [42].

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 [43,44,45,46]. Therefore, supplementation with vitamin D is suggested to attenuate the risk of the cytokine storm, and the severity of COVID-19 [43,47]. 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 [48,49]. 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 [49]. 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 [48]. Furthermore, time required for resolving cough symptoms with D3 supplementation (5000 IU) was significantly shorter compared to the comparison group [48]. 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 [50]. In contrast, a single dose of vitamin D was ineffective for lowering inflammatory markers and for the treatment of patients with severe COVID-19 [51,52,53].

Evidence for the potential role of zinc supplementation for COVID-19 infection is inconclusive [54,55,56]; 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 [57].

It is well known that n-3 PUFAs including eicosatetraenoic acid (EPA) and docosahexaenoic acid (DHA) have anti-inflammatory properties [64,65,66]. 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 in this review investigated the efficacy of n-3 PUFAs for COVID-19 outcomes [59,60,62]. 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 [59]. 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 [60]. 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) [62].

Quercetin—a polyphenol with antioxidant and anti-inflammatory properties—is widely known to have favorable effects on inflammation and infection [67,68,69]. 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) [58]. Furthermore, significant reductions in LDH and ferritin levels were reported in the treatment group vs. control, while hs-CRP remained unchanged [58]. 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 [61].

High quality evidence from systematic reviews and meta-analyses of RCTs, indicates that probiotics may have a favorable role for responses to infections [70]. 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 [63].