Zinc – Zinc deficiency is believed to be slightly prevalent worldwide (+17%), especially among infants and elderly populations or those with metabolic diseases. Chronic zinc deficiency may be associated with impaired immune function, oxidative damage, inflammation and autoimmune disorders (3). As a treatment for COVID-19, zinc is being explored parenterally** for inpatients due to varying oral absorption rates and possible GI side effects. For high risk outpatients, adequate oral zinc intake is recommended, either through dietary intake or supplements. If supplementing, it is important to stay within recommended dietary allowances. (4) Supplementary zinc may only be beneficial when the patient is baseline deficient. (5) Zinc has been experimentally combined parenterally with CQ/HCQ, which are theorized to increase the bioavailability of zinc (ionophore)(4). Zinc is hypothesized to interact (reduce activity) with ACE2 receptors (3). Update 2/14: a study found that high dose Zinc (50mg gluconate) and high dose ascorbic acid (8000mg) or a combination of both did not significantly decrease symptom duration. (23)

Vitamin C – Maintaining adequate vitamin C through dietary intake (or supplements as needed) will allow optimal immune function. Consuming a diet with a variety of plant foods will provide above the DRI for vitamin C along with additional antioxidants and micronutrients. Individuals with acute infections, elevated inflammation, chronic smokers, or the elderly, in addition to those exposed to environmental toxins, may experience increased vitamin C depletion and require higher than typical vitamin C intake for maintenance (9, 10, 11). Intravenously administered vitamin C** can achieve drastically higher plasma concentrations than oral vitamin C and is better tolerated. During inflammatory responses such as ARDS or sepsis, patients experience increased cellular oxidation which blocks vitamin C receptors during a state of increased vitamin C consumption on a cellular level. (decreased vitamin C absorption and depleted vitamin C status) (10) When elderly are deficient in vitamin C, especially those with chronic diseases, they are at increased risk of all cause mortality. Additionally, individuals with vitamin C deficiency are especially susceptible to respiratory infections (11).

Elderberry (S. Nigra)* – Elderberry extract was administered in 15ml increments 4 times/day for 5 days in patients with Influenza A & B infection. The first dose was given within 48 hours of symptom onset. Symptoms were relieved an average of 4 days sooner in the elderberry syrup group than the placebo group. Elderberry syrup is rich in flavonoids, specifically anthocyanins. Anthocyanins may act by preventing viral adhesion to cell receptors, may promote cytokine activity and may have antiinflammatory effects (19). More RTC’s need to be conducted to determine the benefits of elderberry products or anthocyanins on immune health. 

Black Cumin – Thymoquinone, the major bioactive component of black seed essential oil, is hypothesized to reduce activity of ACE2 receptors (1) Nigellimine, a major alkaloid of black seed is believed to share structural similarities to chloroquine and hydroxychloroquine, therefore theorized to increase zinc’s ability to enter pneumocytes (1). Thymoquinone is quickly eliminated and slowly absorbed, which limits its oral use due to low bioavailability (approx. 58% bioavailable). A lethal dose has been determined in mice and rats, but has not been established in humans (2). Further studies need to be conducted to determine potential benefits of black cumin or thymoquinone.

Quercetin – Quercetin is a flavonoid found in apples, onions, honey, berries, red grapes, cherries, citrus fruits, and leafy greens (7). Quercetin acts as an antioxidant (free radical scavenger) and may have anti-inflammatory effects. Sources (dietary and supplementary) have various bioavailability and may be more beneficial with long-term consumption/administration. Vitamin C enhances the antioxidant effects by recycling oxidized quercetin (6). Quercetin acts as an ionophore (enhances effects) for zinc. (8)

Vitamin D3* – Vitamin D3 supplementation showed protective effects from Acute Respiratory Tract Infections in groups with low baseline serum 25-hydroxyvitamin D levels (deficient) more than those with adequate levels, though some protective effects were shown for groups with higher baseline serum vitamin D levels as well. Adult groups received daily or weekly supplementation around 2,000-4,000IU. Supplementation did not reduce risk for serious adverse events or death (any cause) (13). Due to the nature of the pandemic, many preprint studies are being published without peer-review. Until more peer reviewed studies and clinical trials are published, it is unknown whether vitamin D supplementation can reduce risk or severity of COVID-19. Additionally, risk factors for vitamin D deficiency overlap with risk factors for death from COVID-19 (old age, ethnicity, sex, obesity, diabetes, hypertension), however, these correlations do not prove causation (14). The general population should focus on maintaining adequate vitamin D levels for optimal benefits.

Melatonin – Melatonin, a hormone influenced by the pineal gland’s interaction with the light-dark cycle, plays a major role relating to immune function. Melatonin modulates signalling pathways acting to decrease inflammatory activity and also acts as an antioxidant that mediates mitochondrial metabolism. During states of stress, inflammation decreases tryptophan activity (precursor to melatonin), suppressing melatonin production. Additionally, melatonin induces the circadian gene, and during states of viral infection, the circadian rhythm regulates immune response, thus promoting additional viral replication (15). A large-scale data analysis showed an association between melatonin supplementation and reduced likelihood of testing positive for SARS-COV-2, however, large-scale observational studies and random controlled trials are still needed to verify whether melatonin shows clinical benefits for COVID-19 prevention (16).

Probiotics – Mucus membranes act as a defensive barrier, housing antibodies and enzymes, while also housing beneficial bacteria. Probiotics exchange information with immune cells and modulate the vitamin D axis, all playing a role in immune response by maintaining the mucosal barrier and regulating inflammatory response. A relationship has been established between the gut and lung microbiota, and just like probiotics within the gut, lung microbiota protect against infection (22). Dysbiosis can occur when prebiotics are not consumed adequately, bacterial or viral invasion occurs, and/or the integrity of the mucosal barrier is weakened, accompanied by inflammation. One study found that influenza respiratory tract infection (RTI) was reduced in children consuming Lactobacillus Brevis (20). The potential mechanisms for action of probiotics include enhancement to the epithelial barrier, competition with pathogens, or production of anti-microbial substances by microflora. Several strains potentially show benefits when used with RTI’s, Influenza, or pneumonia. These strains include Lactobacillus casei, L. gasseri, L. rhamnosus, L. plantarum, Bifidobacterium longum, B. bifidum, and B. breve (21). 

N-Acetyl Cysteine (NAC) – Can be used as a mucolytic and supports glutathione production. 400-600mg/day is recommended for respiratory infections. Little evidence of toxicity (17). NAC was utilized in an observational study for individuals with community acquired (bacterial) pneumonia (CAP). 1200mg/day for 7 days showed malondialdehyde (MDA), an oxidative stress marker, and tumor necrosis factor-a (TNF-a), an acute phase reactant or inflammatory marker, decreased more than the non-NAC group. The NAC group also showed an increase in total antioxidant capacity content. There was no physical improvement of pneumonia, though the observation period was short. Inhalation of NAC may show a better response in future studies and could show beneficial for those on ventilators (18). 

*It is theoretically recommended to avoid immunostimulatory agents that may increase inflammatory cytokines (specifically IL-1B and IL-18) such as elderberry, medicinal mushrooms, echinacea, and vitamin D when actively infected/experiencing symptoms of COVID-19. (lacks clinical data to support safety – use with caution)(8)

** Please note the difference between clinical parenteral administration of certain supplements, such as vitamin C and zinc, vs oral supplements. Clinical inpatient administration of supplements are typically completely different in regards to dosage and chemical composition when compared with oral supplements and are often accompanied with additional medications such as antibiotics or steroids.

References:

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