COVID-19 treatment: immune support nutrients

Vitamins and minerals. The European Food Safety Authority has found evidence for a causal relationship between intake and optimal immune system function for vitamins A, C, D, B6, B9, B12, zinc, selenium, copper, and iron2,3. Levels of 22+ nutrients have been linked to COVID-19 outcomes4, and multiple nutrient deficiencies are very common4. As with other viruses5-11, 260 clinical studies show that treatment with vitamin A, vitamin C, vitamin D, and zinc12-270 reduces risk for COVID-19, confirmed in multiple additional meta analyses271-302.

Vitamin D. There is extensive evidence linking vitamin D levels with COVID-19 outcomes124,138,142,158,186,188,191,193,198,201,203,217,219,225,303-504. These studies do not establish a causal link—low levels are correlated with other factors that may influence COVID-19 susceptibility and severity. However, the 125 controlled treatment studies78,84,103-225 do show the efficacy of vitamin D (p<0.0000000001), confirmed in multiple additional meta analyses278-296. Vitamin D deficiency is very common, with levels <50 nmol/l for 48% of people worldwide in a meta analysis of 308 studies505. While efficacy for all treatments may vary based on genetics, many studies confirm this for vitamin D438,464,506-520. Studies to date show improved results with calcifediol, calcitriol, and analogs, which avoid long conversion delays with cholecalciferol, with ongoing treatment using multiple doses compared to a single bolus dose, and with acute treatment compared with chronic supplementation—efficacy of prophylaxis may depend on the treatment regimen and other factors521.

High supplement use by healthcare professionals and with higher education. Treatments like vitamin C, D, and zinc were often not recommended by health authorities in contradiction to the clinical evidence. However surveys typically show that use was common, with increased prevalence for healthcare professionals522-524 (and specifically those with more experience525), more highly educated individuals523,526-533, and with higher income525,528,531,532. Research also shows that healthcare professionals had lower risk than expected534,535, consistent with greater use of effective treatments. Physicians may not have prescribed treatments to patients due to local politicization or regulations, however they often used treatments themself522-524,536,537.

Protocols typically combine multiple treatments. No single treatment is guaranteed to be effective and safe for a specific individual. Leading evidence-based protocols combine multiple treatments.

Complementary and synergistic actions. There are many complementary mechanisms of action across treatments, and studies show complementary and synergistic effects with polytherapy112,538-553. For example, Jitobaom et al.539 showed >10x reduction in IC₅₀ with ivermectin and niclosamide, an RCT by Said et al.112 showed the combination of nigella sativa and vitamin D was more effective than either alone, and an RCT by Wannigama et al.554 showed improved results with fluvoxamine combined with bromhexine, cyproheptadine, or niclosamide, compared to fluvoxamine alone. Treatment efficacy may vary significantly across SARS-CoV-2 variants. For example new variants may gain resistance to targeted treatments555-561, and the role of TMPRSS2 for cell entry differs across variants562. The efficacy of specific treatments varies depending on cell type563 due to differences in viral receptor expression, drug distribution and metabolism, cell-specific mechanisms, and the relevance of drug targets to specific cells. Efficacy may also vary based on genetic variants564-567. Variable efficacy across SARS-CoV-2 variants, cell types, different tissues, and host genetics, along with the complementary and synergistic actions of different treatments, all point to greater efficacy with polytherapy. In many studies, the standard of care given to all patients includes other treatments—efficacy seen in these trials may rely in part on synergistic effects. Meta analysis of all early treatment trials shows 68% [57‑77%] lower risk for studies using combined treatments, compared to 33% [30‑36%] for single treatments.

SARS-CoV-2 evolution and the risk of escape mutants suggests treatments with broader mechanisms of action and polytherapy. SARS-CoV-2 can rapidly acquire mutations altering infectivity, disease severity, and drug resistance even without selective pressure568. Antigenic drift can undermine more variant-specific treatments like monoclonal antibodies and more specific antivirals. Treatment with targeted antivirals may select for escape mutations569. Less variant specific treatments and polytherapy targeting multiple viral and host proteins may be more effective.