Nutritional Therapy

Version	Summary	Created by	Modification	Content Size	Created at	Operation
1		Maya Bassil	+ 2859 word(s)	2859	2021-11-24 09:04:45	\|
2	Done	Jason Zhu	+ 1 word(s)	2860	2021-11-30 03:50:12	\| \|
3	Done	Jason Zhu	Meta information modification	2860	2021-11-30 03:51:10	\|

This entry is adapted from the peer-reviewed paper 10.3390/ijerph182212001

With the growing spread of COVID-19 worldwide, the appeal to nutritional therapies in conjunction with medical therapies has been heightened. Promising findings have been reported when medical treatments were complemented with nutritional interventions.

nutritional therapies COVID-19 Vitamin

1. Introduction

Over the past decade, the dietary supplement market has witnessed a hike in sales. Still, several weeks prior to the first COVID-19 wave, sales increased by 44% compared to 5% in the previous year in the United States. Similar trends were detected in the United Kingdom and France, where sales increased by 63% and 40%, respectively. This shift in market demand is attributed to the allegedly “immune-boosting” effects of vitamins and minerals ^[1].

2. Vitamin D

Vitamin D has commonly been found to be inversely associated with the risk of developing acute respiratory viral infections (ARI), rendering it integral in the fight against COVID-19 ^[2]^[3]. A recent review of clinical trials revealed significant associations between in vivo vitamin D supplementation and risk of developing ARI, despite conflicting results in few reports. All studies supplemented their participants with a daily dose 1500 IU of oral cholecalciferol. Interestingly, better clinical results were obtained when vitamin D was administered weekly or daily rather than as a one-time bolus monthly or every three months. Bolus supplementation might dysregulate enzymes responsible for synthesis and degradation of 1,25-dihydroxyvitamin D, thus decreasing its concentrations in post-renal tissues ^[3]. One RCT showed that the supplementation had a protective effect on participants who had baseline serum 25-Hydroxyviatmin D (25(OH)D) below 10 ng/mL by 36% (OR 1.36 95%CI 1.01–1.84), while another showed a 7% risk decrease in self-reported ARI with each 4 ng/mL increase in serum 25(OH)D. Subgroup analysis furthermore indicated that the effect was only significant among participants with serum 25(OH)D below 25 nmol/L (p = 0.002) ^[4]^[5]. A systematic review and meta-analysis of RCTs showed that vitamin D supplementation was a safe protective agent against ARI ^[6].

Emerging epidemiological findings link serum 25(OH)D concentrations to COVID-19 disease incidence or prevalence ^[3]. Two national European investigations showed that lower circulating 25(OH)D was associated with a higher COVID-19 severity ^[7]. D’avolio et al. revealed that patients that tested positive for COVID-19 had a median 25(OH)D of 11.1 ng/dL, while that of individuals who tested negative was 24.6 ng/mL (p < 0.004) ^[7]. Similarly, an observational study in the United Arab Emirates showed that vitamin D levels <12 ng/mL upon hospital admission were associated with a more severe COVID-19 infection (p = 0.005) after adjusting for risk factors (age, sex, smoking, and comorbidities). As for the death risk, after adjusting for age and sex, admitted patients with serum 25 (OH)D <12 ng/mL had a 2.55 times higher risk of death (p = 0.04), which increased to 2.58 times (p = 0.048) when comorbidities were entered into the model ^[8].

Additionally, the role of ethnicity in affecting the relationship between vitamin D status and the likelihood of testing positive for COVID-19 was studied retrospectively by Meltzer et al. Findings revealed that black individuals were 2.64 times more likely to test positive if they had vitamin D levels of 30 ng/mL to 40 ng/mL, while no association was found among white participants ^[4].

Supplementing COVID-19 patients with Vitamin D presents several challenges. Hospitalized patients are already in a hyperinflammatory state, and the effects of micronutrient supplementations might be masked in the presence of medications. Another study on COVID-19 cases examined the association between the serum 25(OH)D levels and clinical symptoms. Cases were classified as: (1) mild–mild clinical features without pneumonia diagnosis, (2) ordinary–confirmed pneumonia with fever and other respiratory symptoms, (3) severe–hypoxia (at most 93% oxygen saturation) and respiratory distress, and (4) critical–respiratory failure. Serum 25(OH)D levels were inversely associated with the severity of clinical outcomes (p < 0.001). The odds of having mild outcomes rather than ordinary were 1.63 times for each increase in standard deviation (SD) of 25(OH)D (p = 0.007). Additionally, for each 1 SD increase in serum 25(OH)D, the odds of having mild outcomes rather that severe was 7.94 times higher (p < 0.001), while the odds of having mild outcomes rather than critical ones was 19.61 times higher (p < 0.001) ^[3]. A systematic review and meta-analysis of 43 observational studies found that the risk of being infected with COVID-19 is inversely related to vitamin D values (OR = 1.26; 95% CI, 1.19–1.34; p < 0.01). Comparing vitamin D deficient patients to non-deficient, the severity of the disease and mortality risk were significantly higher (OR = 2.6; 95% CI, 1.84–3.67; p < 0.01 and OR = 1.22; 95% CI, 1.04–1.43; p < 0.01, respectively) ^[5]. In a double masked RCT, COVID-19 patients on a combination of HCQ (400 mg every 12 h on day one then 200 mg for the following five days) and azithromycin (500 mg orally for five days) were allocated to either no calcifediol or an oral calcifediol of 0.532 mg upon admission. Patients in the intervention were given 0.266 mg of calcifediol on days three, seven, then weekly till discharge. Results showed that including calcifediol in the treatment reduced the need for ICU transfer (OR: 0.03; 95%CI: 0.003–0.25). Among the patients in the intervention group, none died, and all were discharged with no recorded complications ^[9]. Conversely, a randomized clinical trial conducted on 240 hospitalized patients with moderate to severe COVID-19 reported no improvement in hospital stay following a single dose of 200,000 IU of vitamin ^[10]. The latest Cochrane review revealed that to date, not enough good-quality evidence has been found on the use of vitamin D as safe and effective treatment in the fight against COVID-19 ^[10]. Discrepancies in the findings so far could be related to differences in the routes and forms of vitamin D supplementation and in the heterogeneity in subject recruitment in terms of severity of the disease and preexisting (or lack thereof) of diagnosed vitamin D deficiency ^[11]. A recent multicenter RCT showed that a daily 5000 IU dose of vitamin D for two weeks significantly increased serum 25 (OH) D (p = 0.003), and reduced time to recovery (p = 0.039) and aguesia (p = 0.0035) ^[12].

Vitamin D boosts the body in the fight against viral infections in three domains: physical barrier, natural immunity, and adaptive immunity. At the cellular level, the active form of vitamin D preserves the junction integrity between cells that are highly compromised during viral infections. It also decreases the damage inflicted on cells due to the induced cytokine storm and decreases pro-inflammatory cytokines, including TNF and INF gamma (INF-γ), while enhancing the expression of anti-inflammatory cytokines as a result of macrophages. It also enhances innate immunity by releasing antimicrobial peptides; cathelicidin and defensins. Cathelicidin directly attacks enveloped and non-enveloped viruses by disturbing viral cell membranes and neutralizing the biological activity of their endotoxins. With respect to adaptive immunity, the active form of vitamin D suppresses T-1 helper cells, leading to the release of inflammatory cytokines and INF-γ, and enhances the release of T-2 helper cells that inhibit the release of T-1 cells. This induces the release of T regulatory cells that stop any inflammation release. High levels of vitamin D also increase genetic expressions that improve body anti-oxidative capacity and increase the levels of glutathione, sparing vitamin C usage, which is another potent antioxidant ^[4]^[7]^[13]^[14].

3. Vitamin C

Clinical studies have shown the effectiveness of vitamin C as an antiviral treatment in acute respiratory disease syndrome (ARDS). During the SARS outbreak, vitamin C was widely consumed as a preventative measure, and participants who took vitamin C supplements were asymptomatic. A RCT on older adults showed that 200 mg/day of vitamin C improved respiratory symptoms among severely ill patients and recorded 80% fewer deaths when compared to placebo ^[14]. In a case report by Cheng (2020) ^[15], a patient with ARDS was given a dose of 200 mg/kg body weight of vitamin C daily. Significant progress was found in X-ray imaging within 2 days, and 2 months later the patient was cured ^[15].

The countries with the highest COVID-19 cases are low- to middle-income countries known to have high rates of hypovitaminosis C, indicating that vitamin C deficiency can overlap with COVID-19 risk factors ^[16]. Intravenous (IV) pharmacological administration of vitamin C (200 mg/kg body weight/day) divided into four doses in COVID-19 patients, resulted in a 97.8% reduction in ICU stay. Additionally, a drop-in mortality rate was detected reaching 8.5% in the treatment group and 40.4% in the control group (p < 0.001) ^[15]. Additionally, when IV vitamin C was administered to 50 COVID-19 patients with moderate to severe disease intensity, at a dose of 2 to 10 g/day over eight to ten hours, oxygenation index was improved, and all patients were eventually discharged ^[15]. Another study on COVID-19 patients showed that one g of IV vitamin C for three days caused a significant drop in inflammatory markers ^[16]. In the United States (US), ICU patients on a 1500 mg regimen of vitamin C (four times per day) showed significant improvements compared with patients not receiving supplementations ^[17]. Another cohort study on 76 COVID-19 patients stratified them to either receive 6 g vitamin C every 12 h on the first day and 6 g once a day for the next four days or standard therapy. Participants receiving vitamin C had a reduced 28-day mortality risk (HR = 0.14, 95% CI, 0.03–0.72) and improved oxygen status (63.9% for vitamin C group versus 36.1% for the standard therapy group) ^[18]. Among ICU-admitted COVID-19 patients, the majority had hypovitaminosis C (mean level below 22 µmol/L). The mean level of vitamin C for survivors was 29 µmol/L, while levels were 15 µmol/L for non survivors ^[19]. Consistently, a study in New Zealand showed that pneumonic COVID-19 patients had significantly lower vitamin C levels compared to healthy patients (p < 0.001) ^[19]. However, not all studies found a significant effect of vitamin C on COVID-19. A randomized open label clinical trial randomized participants to either receive ritonavir and HCQ or high dose of intravenous vitamin C (6 g per day) with the same regimen. The length of hospitalization among participants receiving vitamin C was significantly longer than those on the traditional regimen (8.5 days versus 6.5 days respectively) (p = 0.028). Additionally, upon discharge, no significant difference between clinical outcomes (length of stay, mortality, and oxygen saturation) was detected ^[20].

ARDS is accompanied by high oxidative stress due to excessive release of free radicals and cytokines that will ultimately result in cellular and organ damage, in addition to lung capillary endothelial cell activation and neutrophil infiltration. It also leads to a state of hypoxia and damage to the alveoli. Being a potent antioxidant, vitamin C shows protective mechanisms against these injuries. Furthermore, in pharmacological doses, vitamin C becomes a pro-oxidant, enhancing the release the hydrogen peroxide which targets viruses by improving chemotaxis. Vitamin C can also promote phagocyte progression, oxidative death, and lymphocyte proliferation, all of which render vitamin C a potential defense in the management of COVID-19 ^[21]. Severe cases of COVID-19 can lead to endothelial damage that can deteriorate the health status of patients. Vitamin C can reduce the risk of complications by restoring cells’ endothelial functions ^[19].

4. Zinc

Zinc (Zn) is known to be a potent antiviral, antibacterial, and immunoregulatory micronutrient ^[21]. Zn is supplemented as part of the treatment of coronavirus ^[5], particularly in the most common protocols using chloroquine (CQ) or hydroxychloroquine (HCQ) with azithromycin. Indeed, a large study on patients with COVID-19-like symptoms included 220 mg Zn sulfate once daily in addition to HCQ 200 mg twice daily and azithromycin 500 mg once daily, for a total of 5 days ^[22]. High intracellular Zn was shown to increase the efficiency of CQ and HCQ on the inhibition of RNA-dependent RNA polymerase (RdRp), which is an essential protein encoded in the genomes of RNA viruses ^[22]. CQ and HCQ act as weak bases that disrupt the cellular signaling of lysosomes and Golgi. They work by increasing lysosomal pH; thus, the bioavailability of these drugs largely relies on protonization with Zn²⁺ to increase their affinity to low pH organelles ^[21].

However, no association between Zn intake and the risk of developing ARI was observed in a cohort study on women for Zn intakes above of 7.5 mg/day. A higher Zn intake was associated with an increased risk of developing ARI (CI 95%, 1.04–2.16) at levels above 10 mg/day among men due to Zn becoming a pro-oxidant ^[23].

Zn antiviral properties are mediated through its elevated intracellular concentrations. Zn modulates the structure of viral proteins and was found to directly work on the RNA of SARS by reducing its replicative abilities. Several drugs, including disulfiram, promote Zn release from papain-like protease in MERS and SARS, causing protein destabilization. In addition, COVID-19, much like SARS, needs ACE2 to enter target cells, and Zn levels of 100 µM have been shown to reduce ACE2 activity in the lungs of rats. Consistently, Zn supplementation in animals has resulted in significant improvements in lung epithelium by enhancing muco-ciliary clearance, cilia length, and tight cellular junctions (improving barrier functions) ^[24].

A retrospective study on hospitalized COVID-19 patients showed that patients with serum Zn levels <50 µg/dL had more severe clinical presentations and higher inflammatory markers: CRP (p = 0.03), IL-6 (p < 0.001). Having serum Zn < 50 µg/dL increased the risk of mortality by 21%, while having higher values had a 5% risk mortality (p < 0.001) ^[25].

Hospitalized COVID-19 patients receiving Zn supplements exhibited reduced hospital mortality by 24% and were discharged home sooner (p = 0.003). A prominent feature of COVID-19 is the loss of taste and smell attributed to the destruction of sensory cells or viral entry to the brain. Zinc deficiency has been directly associated with a reduction in the sense of taste; thus, zinc supplementation has been reported to be favorable to chemosensory abilities. Other studies, however, showed no association between Zn supplementations and olfactory dysregulations ^[26].

More recently, Ali et al. retrospectively assessed the role of Zinc in COVID-19 prevention and mortality among Asians and Europeans. Zinc deficiency was two times higher among Asians (17.5%), which could have led to a significant positive association between zinc deficiency and COVID-19 (p < 0.05), but not with mortality. Among the European population, zinc deficiency was less likely to be detected (8.9%), and a significant negative correlation was found between COVID-19 cases and death per million (p < 0.05) ^[26]. In another recent study, investigators found that COVID-19 patients who died had lower plasma zinc (43 μg/dL) compared to those who survived (63.1 μg/dL). This was reflected in an inverse relationship between plasma zinc upon admission and mortality, whereby for every unit increase in plasma zinc there was a 7% reduced risk of in hospital mortality. Plasma zinc less than 50 μg/dL at admission was associated with a 2.3-fold increased risk of mortality. In line with this, a study in Japan on 62 COVID-19 patients found that serum zinc was predictive of disease severity ^[25].

5. Other Nutrients and Phytochemicals

Selenium (Se) is a potent antioxidant. A daily 100 mcg intake of Se has shown positive effects in fighting viral infections (including SARS and H1N1) ^[4]. Studying Se status in different regions in China showed that in areas known to have a high Se status, higher rates of cure among victims were detected, and vice-versa ^[25]. A cross-sectional study in a German hospital showed that 64.7% of deceased COVID-19 patients were Se deficient, whereas only 39% of those that were Se deficient survived ^[27]. Se supplementation was associated with a significant reduction in viral mutations and a boosted immunocompetency in patients with known Se deficiency. Se activates T cell multiplication, thus enhancing the innate immune system and affecting thyroid hormone ratios that are a part of developing cellular immunity and cytokines ^[28].

A meta-analysis reported that upper respiratory tract infections (URTI) were similar in groups supplemented with flavonoids and the control group, indicating an absence of association (0.83 95%CI, 0.75–1.11). Four studies have reported that sick days were also similar between both groups (p = 0.16). However, supplementations with flavonoids in cohort studies significantly decreased missed workdays (p = 0.035) and symptoms (p < 0.001) compared to control ^[29]. Flavonoids have antiviral mechanisms; quercetin and hesperidin have anti-replicative effects, while quercetin and catechin have anti-infective effects. Flavonoids have a high binding affinity to the spike proteins and ACE2 receptors on the novel coronavirus, causing a conformational change that inhibits viral entry. Compared to CQ, flavonoids were found to be equally or even more potent in binding to the virus ^[29]. Different flavonoids are involved in ACE1 and ACE2 inhibition via several mechanisms ^[28]. Quercetin inhibits proteases, while kaempferol interacts with ACE2 via a method that inhibits viral entry. Flavonoids protect the body against ROS and their having affinity to hydrophilic amino acids aids in repairing any viral induced cell damage ^[27]. Moreover, vitamin C has been shown to have synergistic antiviral properties when given with quercetin ^[16]. Adequate flavonoids can be achieved from several good sources (100 g/serving) such as 250 mL of green tea, 100 g dark chocolate, and 100 g blueberries ^[30].

Curcumin is known to be an antioxidant, anti-inflammatory, and immunomodulatory natural molecule. Curcumin has shown good binding affinity with the virus’ nucleocapsid, a pro-inflammatory protein. The structure RNA of COVID-19 was determined to have a groove between the palm and finger regions at the RNA binding site, with curcumin showing a binding affinity to this region. It also might inhibit the nucleocapsid and suppress components of cellular signaling pathways that aid in infected cells growth by inhibiting protein kinases and activating enzyme cyclooxygenase ^[31]. The antiviral properties of curcumin stem from their ability to act in cellular signaling pathways (apoptosis and inflammation) and interfere in the viral replication cycle (genome replication and viral attachment) ^[32]. Curcumin may modify the surface protein structure, thus inhibiting entry of virus and budding. It can also affect the protein membrane by altering the host cell’s lipid bilayer composition ^[33]. A new study showed that curcumin has a binding affinity to two proteins that are involved in the adhesion, fusion, and entry of the corona virus ^[33].

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