To date, 1 in 378 people in the United States have tested positive for COVID-19 as communities are experiencing a seemingly exponential rise in cases with no end in sight. Healthcare systems in many parts of the United States are at a breaking point as nationwide hospitalizations for COVID-19 have increased by nearly 22% with deaths up 23% in just the last 2 weeks. With identified cases up 71% in the same amount of time and hospitals that are already at full capacity leading into a winter cold and influenza season, it is imperative we focus some attention on how to treat patients with mild to moderate symptoms outside of the hospital and to limit the progression of disease severity.
There has been extensive biomedical research devoted to finding drugs that could mitigate the devastation of this pandemic. It is important to highlight here that the only “proven” prescription medication to date in the treatment of COVID-19 is corticosteroids, and this benefit is only seen in patients who are requiring supplemental oxygen or who have a history of underlying COPD or Asthma who present with symptoms of exacerbation. Unfortunately, pharmaconutrition and other readily available over-the-counter medications have not received their due platform of exposure, and they should.
In October 2020, the Front Line COVID-19 Critical Care Alliance developed the I-MASK+ Prophylaxis and Early Outpatient Treatment Protocol for COVID-19. While this has not been widely adopted, there are certainly some very strong points to be made about this proposed protocol that warrants some exposure.
So, let’s dive into the evidence…
Vitamin C
There is a close link between Vitamin C, or ascorbic acid, and the immune system. Vitamin C acts as an anti-oxidant that protects proteins, lipids, and nucleotides from oxidative damage. Vitamin C is found in high concentrations inside leukocytes and during times of infection, this Vitamin C store becomes rapidly depleted. In the absence of antioxidant defenses, pro-inflammatory pathways progress unchecked, which leads to increased severity of viral infections. While Vitamin C deficiencies are very rare in the United States, several studies have shown patients with severe respiratory infections, such as pneumonia, have deficiencies in Vitamin C and supplementation decreases disease severity and duration. Many patients with COVID-19 have elevated levels of the pro-inflammatory cytokine IL-6. IL-10 is an anti-inflammatory cytokine that blocks production of IL-6. Studies have shown that 1 g/day of Vitamin C increases the anti-inflammatory cytokine IL-10, which has been suggested as a critical component in potentially blocking the cytokine storm seen during COVID-19 infections (Shakoor, 2020).
NIH guidelines suggest there is insufficient evidence to recommend either for or against the use of Vitamin C in the outpatient treatment of COVID-19. Further, the use of high dose IV Vitamin C administration in critically ill patients with non-COVID-19 related Sepsis and ARDS have provided mixed results in literature. In a 2013 meta-analysis looking at effects of oral Vitamin C supplementation in patients with the common cold, the duration of symptoms was reduced by 8% in those taking > 0.2 g/day.
My take: There is a lack of documented benefit to Vitamin C. It is also important to remember that Vitamin C is a water-soluble vitamin. That essentially means that absorption will be determined on need by the body. According to the NIH, at doses of over 1 g/day, less than 50% of the vitamin will be absorbed, and the rest will be eliminated in the urine. However, at standard doses; Vitamin C seems to be a reasonable micronutrient to supplement during times of illness to maintain adequate body stores. Just don’t go crazy with it…
Vitamin D
If you live north of the equator, there is a good chance that you are deficient in Vitamin D, especially during the winter months as sun exposure creates Vitamin D in the body. Several mechanisms have been described to explain how Vitamin D can reduce the risk of different infections including cathelicidins and defensins that can lower viral replication and reduce por-inflammatory cytokines that could play a factor in the dreaded cytokine storm (Grant, 2020).
In a study of 235 patients hospitalized with severe COVID-19 infections, 75% of those patients with severe disease were deficient in Vitamin D. Further, those who had adequate Vitamin D levels were 51.5% less likely to die from their illness (Maghbooli, 2020). Similarly, a study of 42 patients with acute respiratory failure from COVID-19 showed 81% of patients were deficient in Vitamin D. In this study, patients who were deficient have a 50% probability of death versus just 5% in those with levels > 10 ng/mL (Carpagnano, 2020). Finally, a study of 185 patients with COVID-19 showed those deficient in Vitamin D had 6X increased risk of needing mechanical ventilation and over 14X increased risk of death than their non-deficient counterparts (Radujkovic, 2020). It has been hypothesized that this may explain why regions in the northern United States have higher mortality rates than those seen in southern states (Rhodes, 2020).
Further, there is some evidence that adequate levels of Vitamin D may have some preventative effects. In a study of ~192,000 patients from March to June, those who were deficient in vitamin D had a 54% higher positivity rate of COVID-19 than those who had adequate levels (Kaufman, 2020). Vitamin D supplementation has been shown to decrease the rate of other seasonal respiratory infections such as Influenza by 7% for each 4 ng/mL increase in Vitamin D blood levels (Kaufman, 2020).
According to the NIH, sun exposure of 5-30 minutes daily to the face, arms, hands, and legs without sunscreen is usually enough to maintain Vitamin D stores. However, supplementation of 1,500-2,000 IU daily may be required to maintain stores in those at risk of deficiency. I’m talking to you Michigan. It is important to note that the NIH does not recommend doses over 4,000 IU daily for adults due to concern of Vitamin D toxicity.
My take: There have been no controlled trials looking at effects of Vitamin D supplementation in COVID-19. While there are a number of ongoing clinical trials, guideline-based recommendations have not been given. However, there does appear to be some merit to Vitamin D deficiency and risk of different illnesses, including COVID-19. While the NIH guidelines suggest there is insufficient data to recommend either for or against the use of Vitamin D for prevention or treatment of COVID-19, it is reasonable to recommend Vitamin D supplementation to populations at risk of deficiency, particularly during the winter months. It is also important to point out that unlike water-soluble Vitamin C, Vitamin D is fat-soluble. This means it is not freely excreted in the urine if higher doses are ingested. Instead, it will be stored in the liver and fatty tissue and excessive intake can build up in the body, which can be dangerous. So, please do not take more than the recommended daily value.
Melatonin
Most people are well aware of Melatonin’s role in regulating the sleep-wake cycle. What you may not know is it also has potent anti-oxidant, anti-inflammatory, and anti-apoptotic properties shared by its precursor N-acetylserotonin and down-stream metabolites (Kleszczynski, 2020). Animal models of sepsis have shown Melatonin can prevent multi-organ dysfunction and reduce cytokine production (Colunga Biancatelli, 2020). The way in which this happens is a bit outside of the scope of this article, but you can read more about it here if you really miss biochemistry. Further, Melatonin has been shown to have anti-viral actions against several other viral infections, including Ebola (Boga, 2012; Reiter 2020).
My take: Melatonin is inexpensive, non-toxic and has shown no harmful adverse effects in humans. If there is even a possibility it could play a role in preventing cytokine storm, count me in…
Zinc
Zinc is a key trace mineral, involved in many biological processes including immune responses to viral infection. Zinc deficiencies have been shown to alter protective barriers in lung tissue and cause cell death in lab studies. Further, Zinc deficiencies lead to increased inflammatory cytokine production and altered protective barriers in lung tissue. Studies have shown at least partial improvement in these features with supplementation (Shakoor, 2020). Further, Zinc has been shown to inhibit the replication of other Coronaviruses, Poliovirus, and Influenza (Aartjan, 2010; te Velthuis, 2010). Studies of patients with Zinc deficiency has shown an increased risk of organ dysfunction and death in sepsis (Hoeger, 2017). In a prospective study of 49 patients admitted to the hospital with COVID-19, those with Zinc deficiency had a higher rate of complications, were more likely to develop ARDS (18.5% vs 0%), were more likely to receive steroids, and had a higher mortality rate (18.5% vs 0%) (Jothimani, 2020).
Early studies on the benefit of Zinc in viral upper respiratory tract infections have been rather mixed. However, a 2006 Cochrane review of Zinc on the common cold suggests a benefit when taken within 24 hours of symptom onset (Evans, 2006). When combined with Vitamin C, Zinc has been shown to significantly decrease symptoms of the common cold compared to a placebo (Maggini, 2012). A 2017 meta-analysis showed that Zinc lozenges shortened the mean duration of colds by 33% (Hemila, 2017). Zinc acetate and Zinc gluconate appear to be the most effective formulations in treating the common cold (Eby, 2004; Eby, 2010). One retrospective study specific to COVID-19 and the use of Zinc in hospitalized patients suggests a possible mortality benefit in patients who receive Zinc prior to needing ICU admission (Carlucci, 2020).
The recommended daily intake of Zinc is 11 mg/day for men and 8 mg/day for women and Zinc toxicity has been documented in literature. Chronic intake of > 150 mg daily has been associated with copper deficiency, altered iron function, and reduced immune function. Studies have shown that reductions in copper can be seen with intakes of just 60 mg daily taken over 10 weeks (NIH). The upper intake levels as recommended by the NIH is 40 mg/daily for both men and women. A recent case series of 4 COVID-19 patients treated with high-dose Zinc salts (up to 200 mg daily) was associated with a significant improvement in objective and symptomatic disease within 24 hours of initiating the high-dose therapy (Finzi, 2020). No adverse effects of the high-dose therapy was reported in this study and elemental Zinc doses up to 216mg/day have been well tolerated in clinical trials for the common cold (Eby, 2010). Upset stomach and metallic taste being the only reported side effects.
The NIH recommends against the use of Zinc supplementation above the recommended dietary allowance for prevention of COVID-19 given the limited evidence at present. The I-MASK+ protocol suggests dosing as elemental Zinc, which is significantly higher than the daily recommended value as well as the upper intake level. However, higher doses used for a short period of time are unlikely to cause significant toxicity and is generally considered safe (Prasad, 2000). I would limit the use to as short a duration as possible.
However, higher doses used for a short period of time are unlikely to cause significant toxicity, as this is rather rare. Regardless, it is important to understand that not all Zinc supplements are the same as different salt forms provide different amounts of elemental Zinc…so be careful!
My take: There isn’t exactly a ton of robust evidence of benefit with Zinc supplementation in COVID-19. However, benefit in other viruses has been documented and it is reasonable to suggest there may be some benefit. It is reasonable to recommend short term Zinc supplements at the recommended daily doses. Just be careful which formulation you are recommending. Higher doses are unlikely to cause toxicity in the short term. Just understand that these doses are not backed by current guidelines. Further, it is important to understand that the absorption of certain antibiotics (Fluoroquinolone and Tetracycline) are inhibited by Zinc co-ingestion. The NIH recommends taking these antibiotics at least 2 hours before or 4-6 hours after taking a Zinc supplement. Further, Thiazide Diuretic use decreases Zinc absorption by nearly 60%, and this should be considered when determining dosing.
B-Complex Vitamins
The common theme to this article is to propose safe ways to suppress aberrant immune activation, which leads to the dreaded cytokine storm phenomenon seen in COVID-19 infections. B Vitamins modulate immune response by down-regulating pro-inflammatory cytokines and inflammation, reduced breathing difficulty, and gastrointestinal problems, preventing hyper-coagulability, potentially improving outcomes and reducing the length of stay in the hospital for COVID-19 patients (Shakoor, 2020).
Specific immunologic effects of B Vitamins: (Calder, 2020; Shakoor, 2020)
- B1 (Thiamine): Deficiency increases inflammation and leads to aberrant antibody responses
- B2 (Riboflavin): Induces irreversible damage to DNA/RNA of different pathogens, rendering them unable to replicate
- B3 (Niacin): Decreases the pro-inflammatory cytokines, IL-1β, IL-6 and TNF-α
- B5 (Pantothenic Acid): Decreases inflammation and improves mental health
- B6 (Pyridoxine): Deficiency is associated with decreased lymphocyte count and function
- B9 (Folic Acid): Deficiency is associated with decreased lymphocyte count
- B12 (Cobalamin): Deficiency decreases effectiveness of neutrophils, decreased lymphocytes and NK cell activity
Thiamine also acts as a carbonic anhydrase inhibitor. It is theorized that lung injury from COVID-19 is similar to that seen in high-altitude pulmonary edema and high doses of Thiamine may have the potential to limit hypoxia and decrease hospitalization in these patients (Shakoor, 2020). However, further studies are needed to verify this hypothesis. Riboflavin has been shown to decrease viral titers of the SARS-CoV-2 virus below the limit of detection (Ragan, 2020). Niacin appears to target IL-6, making it an ideal candidate in protection against the IL-6 mediated cytokine storm and is a reasonable adjunct in the treatment of COVID-19 patients (Liu, 2020). Pyridoxine has been shown to increase the anti-inflammatory cytokine IL-10, which is thought to suppress the T-Cell response responsible for the cytokine storm seen in COVID-19 (Mikkelsen, 2019). In a recent preprint report, Folic Acid was noted to inhibit furin, which prevents entry of the SARS-CoV-2 virus into cells as well as virus turnover (Sheybani, 2020). In one study of patients over the age of 50 admitted to the hospital with COVID-19, a cocktail of Vitamin D3 1,000 IU, Magnesium 150 mg, and Vitamin B12 500 mcg at admission was associated with a decrease in the need for oxygen therapy and ICU admission (Tan, 2020).
My take: Adequate B-Vitamin intake is necessary for a proper functioning immune system. B-Vitamin deficiencies are associated with an increase in pro-inflammatory cytokines that leads to increased cytokine induced inflammation, increased respiratory distress, gastrointestinal problems, and increased clotting potential. While there are no large randomized controlled trials looking at the effects of B-Complex Vitamins during an active COVID-19 infection, it is reasonable to consider supplementation as a cost-effective and safe potential therapeutic option as B-Vitamins are water soluble and therefore toxicity is an unlikely concern.
Pepcid and Zyrtec
Pepcid (Famotidine) is an over-the-counter Histamine-2 receptor blocker commonly used to suppress acid production in the stomach.
In COVID-19, it is theorized that histamine is one of several compounds released during the inflammatory phase of the infection that leads to damage to lung epithelial cells resulting in the loss of regulation of fluid transfer at the level of the alveolus and ultimately contributing to pulmonary edema (Malone, 2020). Lab studies have shown Pepcid to inhibit human immunodeficiency virus (HIV) replication (Bourinbaiar, 1996). Further, Pepcid has been shown to inhibit viral replication of SARS-CoV-2 in lab studies (Wu, 2020).
Several studies have suggested benefit with the use of Pepcid in hospitalized patients with COVID-19 infections. In a retrospective study of 1,620 patients admitted with COVID-19 infections not requiring intubation, Pepcid use was associated with a 2-fold reduction in clinical deterioration leading to intubation or death (Freedberg, 2020). Interestingly, there was no protective effect seen with the use of PPI’s (i.e. Omeprazole) or other H-2 blockers besides Pepcid. In another retrospective study of 878 patients hospitalized with COVID-19, Pepcid was associated with a decreased risk of in-hospital mortality and combined death or intubation (Mather, 2020). However, in a contradictory retrospect study of 1,816 patients admitted to the hospital, Pepcid use was found to not reduce the risk in these outcomes (Shoaibi, 2020).
There is more than one histamine pathway. So, can a combination of Histamine-1 and a Histamine-2 receptor blocker improve COVID-19 outcomes? In a proof-of-concept study using the H-2 blocker Famotidine (Pepcid) 20 mg twice daily with the H-1 blocker Cetirizine (Zyrtec) 10 mg twice daily, patients admitted to the hospital with COVID-19 who received a combination of these drugs (Oral of IV) for at least 48 hours had a lower rate of intubation (7.3% vs 41.7%), lower mortality (15.5% vs 41.7%), and shorter hospital stays (11 days vs 18 days) than those who did not receive these medications (Hogan, 2020). While this association should be interpreted with caution outside of a randomized controlled trial adjusted for cofounders, the data seems impressive at first glance.
My take: Pepcid and Zyrtec are historically safe medications. Current evidence appears to tip in favor of its utility as an adjunctive medication in hospitalized patients and a reasonable intervention to consider in the outpatient treatment of patients with mild symptoms, especially given our current absence of other favorable treatment options.
Aspirin
Aspirin has a theoretical benefit for its anti-platelet, anti-inflammatory, and anti-pyretic effects. Studies have shown that Aspirin has in vitro anti-viral activity against Influenza A, human rhinoviruses, and human cytomegalovirus (Glatthaar-Saalmüller, 2016; Speir, 1996). Multiple studies are currently enrolling and assessing the effects of Aspirin in COVID-19 (NCT04365309, NCT04343001, NCT04363840, NCT04333407). In a recently published study of 412 critically ill patients admitted with COVID-19, Aspirin use was associated with less mechanical ventilation (35.7% vs 48.4%), lower rate of ICU admissions (38.8% vs 51%), but found no difference with in-hospital mortality (Chow, 2020).
It is well known at this point that patients with COVID-19 are at an increased risk of DVT and pulmonary embolism. Current documented rates of embolic disease in hospitalized patients with COVID-19 ranges from 20-69% and nearly 15% of these events lack symptoms (McManus, 2020).
My take: While future research should focus on potential preventative effects of Aspirin and its effects on disease severity, particularly in patients being discharged home from the ER, it seems an obvious treatment option to recommend to patients given the lack of any real identifiable downside. Given there are no patient specific contraindications to its use.
Home Oxygen Monitoring
Patients who do not meet criteria for hospital admission, but have co-morbidities or other risk factors for clinical deterioration (abnormal chest x-ray, increased but not highly abnormal inflammatory markers, symptoms before the 7-11 day period in which the pulmonary inflammatory phase is seen) should be counseled on home pulse oximetry monitoring. There are innumerable reports of patients who develop low oxygen levels in the absence of corresponding symptoms. Identifying these patients before they have clinical deterioration is paramount.
Home pulse oximeters are fairly low cost (around $15-$30) and can serve as a diagnostic tool when used appropriately. Patients should be educated on the fact that pulse oximeters can give false readings and several measurements should be taken to verify an accurate reading. They can be purchased online or at just about every drug store or large grocery store. Healthcare systems that have the means to educate and discharge patients with certified pulse oximeters should employ this approach. However, this is unlikely a feasible option for most community hospitals. Smart phone applications have not performed well in literature at accurately detecting hypoxia, and I do not recommend these be used for home monitoring (Luks, 2020).
A baseline or ambulatory pulse oximetry reading <94% should be used as the threshold to return to the ER (Luks, 2020).
In Conclusion...
Most patients with mild symptoms will have an uncomplicated disease course at home. The over-the-counter medications, when used appropriately, are very reasonable options to possibly help limit the risk of disease progression. My hospital system currently uses the below treatment recommendations for at risk patients being discharged from the ER.
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