Evidence Supporting a Phased Immuno-physiological Approach to COVID-19 From Prevention Through Recovery

May 14, 2020 10 Comments



This paper presents an evidence-based strategy for improving clinical outcomes in COVID-19. Recommendations are based on the phases of the disease, because optimal interventions for one phase may not be appropriate for a different phase. The four phases addressed are: Prevention, Infection, Inflammation and Recovery. Underlying this phased approach is recognition of emerging evidence for two different components of pathophysiology, early infection and late stage severe complications. These two aspects of the disease suggest two different patterns of clinical emphasis that seem on the surface to be not entirely concordant. We describe the application of therapeutic strategies and appropriate tactics that address four main stages of disease progression for COVID-19. Emerging evidence in COVID-19 suggests that the SARS-CoV-2 virus may both evade the innate immune response and kill macrophages. Delayed innate immune response and a depleted population of macrophages can theoretically result in a blunted antigen presentation, delaying and diminishing activation of the adaptive immune response. Thus, one clinical strategy involves supporting patient innate and adaptive immune responses early in the time course of illness, with the goal of improving the timeliness, readiness, and robustness of both the innate and adaptive immune responses. At the other end of the disease pathology spectrum, risk of fatality in COVID-19 is driven by excessive and persistent upregulation of inflammatory mechanisms associated with cytokine storm. Thus, the second clinical strategy is to prevent or mitigate excessive inflammatory response to prevent the cytokine storm associated with high mortality risk. Clinical support for immune system pathogen clearance mechanisms involves obligate activation of immune response components that are inherently inflammatory. This puts the goals of the first clinical strategy (immune activation) potentially at odds with the goals of the second strategy (mitigation of proinflammatory effects). This creates a need for discernment about the time course of the illness and with that, understanding of which components of an overall strategy to apply at each phase of the time course of the illness. We review evidence from early observational studies and the existing literature on both outcomes and mechanisms of disease, to inform a phased approach to support the patient at risk for infection, with infection, with escalating inflammation during infection, and at risk of negative sequelae as they move into recovery.

Four Phases of COVID-19

Clinicians will encounter patients in one of four phases of COVID-19, each requiring its own focus.

Prevention - support is focused on immune surveillance efficiency and reduction of baseline levels of inflammation, to improve outcomes if the patient becomes infected,

Infection - support emphasizes immune activity against infection,

Escalating Inflammation - support is focused on anti-inflammatory measures, and

Recovery - support is focused on resolving inflammation, inhibiting fibrosis and other forms of tissue damage, curtailing losses of function, and restoring and reoptimizing function. Because patients have been observed to relapse into the Escalating Inflammation Phase, it is essential for clinical surveillance to continue well into what may appear to be the Recovery Phase.

1. Foundational Support

To address foundational support, clinicians can consider addressing factors that impact immunological integrity as well as factors that drive non-purposeful inflammation.

Address factors known to impact immunological integrity

Sleep - Healthy sleep is anti-inflammatory and promotes appropriate Th1 response. Disordered sleep is characterized by reduced sleep efficiency, less slow wave sleep, and more REM sleep. Disordered sleep yields increased inflammation and increases Th2 response at the expense of Th1 response.66

Sound sleep hygiene practices, reviewed elsewhere,140-143 are fundamental for promoting healthy sleep. In addition, substances such as melatonin may be added to enhance sleep promotion. Not only is melatonin a useful sleep aid, it also inhibits NLRP3 inflammasome activation,144-146 and reduces airway inflammation.147 Melatonin has also been identified as a potential therapeutic drug in an in silico model of the human interactome with SARS-C0V-2 (4).

Stress - As referenced earlier, stress chemistry is inflammatory and has been shown to shift the patient away from effective Th1 response. Many patients will have been enduring significant chronic stress by the time they become infected. Though it is not part of the main protocol, for patients with significantly elevated stress levels, it may be useful to give adaptogens like ginseng or ashwagandha.148-152

Stress chemistry can and should also be addressed by a number of other techniques that have proven useful for decreasing the stress response. Patient ability and personal preferences will guide the appropriate choices. Techniques include mindfulness-based stress reduction (MBSR)153,154 exercise,155 relaxing music, creative pursuits, biofeedback,156 and many others, reviewed elsewhere.157

Supporting levels of vitamins, minerals, and other substances with known immunological roles. 

The role of nutritional agents as immune modulators has recently been reviewed.185 It's noteworthy that many of these nutrients play dual roles in immunology, supporting immune surveillance while also reducing inflammation.

Vitamin D - The potential utility of vitamin D in COVID-19 has been reviewed, with the authors recommending a multi-day loading of 10 000 iu qd and a steady dose of 5000 iu qd, with the goal of bringing lab ranges above 40-60 ng/ml.186 Many studies have shown that vitamin D deficiency not only impairs immune function but also promotes excessive inflammatory reactions. The role of vitamin D in inflammatory and autoimmune disorders has been extensively reviewed, including here.187 Deficiency has been shown in many inflammatory and autoimmune diseases such as asthma,188 various types of arthritis,189 SLE,190 Type 1 diabetes,191 Multiple Sclerosis,192 among others. Supplementation is most likely primarily effective in those deficient in vitamin D or with a VDR polymorphism impairing vitamin D absorption and metabolism.193

A meta-analysis of studies on vitamin D and acute lung injury (ALI) found that, in studies that did not use very large, rare bolus dosing, vitamin D was safe and protected against ALI. Patients who were deficient and received non-bolus dosing had the most benefit.194 Vitamin D has been shown to prevent experimental lung fibrosis and predict survival in patients with idiopathic pulmonary fibrosis, via inhibition of TGF?.138 TGF? is a central player in lung fibrosis and a central generator of the NETosis discussed above, that is associated with sepsis, thickening mucous secretions, and thrombus formation. Vitamin D has also been shown to reduce the risk of acute respiratory infection.195

Vitamin D is necessary for the formation of macrophage lysosomal enzymes, a key component of the ability of macrophages to kill pathogens, including viruses, that have been engulfed by phagocytosis.196 In many experimental models, macrophages are infected with pathogen in vitro, and the cytokine profiles the macrophages generate are measured. As described in the work of Hewison,196 healthy macrophages with adequate vitamin D status will respond more effectively to infection. This includes greater production of cytokines whose function is to stimulate chemotaxis of neutrophils and other immune elements to the site of infection. Effective neutrophil chemotaxis is induced by inflammatory cytokines, and neutrophil influx into tissue is at the center of normal anti-pathogenic inflammation. These chemical signals are normal in the context of a well-orchestrated inflammatory response, including the resolution phase. Isolating the role of vitamin D in allowing macrophages to respond normally to pathogens does not reflect the total picture of vitamin D's role in the body. Vitamin D plays a key role in both immune system antipathogenic function and anti-inflammatory functions.

Vitamin A - Vitamin A was the first fat-soluble vitamin to be identified. Early researchers found that young animals fed a diet deficient in natural fats became very unhealthy and that their eyes became severely inflamed and infected. Vitamin A was once known as the "anti-infective vitamin," and vitamin A status is a major determinant of overall immune status. Those deficient in vitamin A experience impaired antibody response, decreased levels of helper T cells, and impaired integrity of the mucosal linings of the respiratory and gastrointestinal tracts. Vitamin A-deficient individuals are more susceptible to infectious diseases, respiratory conditions like asthma and allergies, and have higher mortality rates.197

The prevalence of deficiency is difficult to determine as numbers vary widely worldwide and criteria are inconsistent. Nonetheless, deficiency is common worldwide, with epidemic prevalence in Saharan Arica (48%) and South Asia (44%).198

Unfortunately, vitamin A deficiency is also common in the US with 34% of adults consuming less than the EAR.199 Co-author Pizzorno in an unpublished study of retinol levels in 200 adult oil field workers in Canada found that 40% were deficient.

While beta-carotene is commonly considered synonymous with vitamin A, this an error with significant clinical consequences, especially for vegans. Emerging research has shown multiple, surprisingly common, genomic variations that impair conversion of beta-carotene to vitamin A by 24 to 57%. Single nucleotide polymorphisms have been identified that decrease activity of 15,15'-monoxygenase, the key enzyme converting beta-carotene to retinol. rs12934922) and rs7501331 variants have been found in 42% and 24%, respectively. Those with one copy of the less common allele have shown a 32% drop in activity, while those who are homozygous for the polymorphism experience a 57% reduction in conversion rate.200

A controlled animal study in calves found that low dietary vitamin A impaired IgG1 titers against intramuscularly inoculated inactivated bovine coronavirus vaccine.201

Vitamin A levels drop during various types of infection and multiple studies have shown that vitamin A supplementation improves resistance and recovery rate.202 Given the numbers above regarding the high prevalence of vitamin A deficiency, this is cause for concern in the current crisis.

Vitamin A, especially when in balance with vitamin D, has low toxicity except at high dosages. For adults, toxicity is typically seen after 100 000 IU/d for 6 months.203 A study that looked at the positive effects of multivitamin supplementation in women with HIV showed that Vitamin A was detrimental to outcome.204 However, in this study, vitamin A was supplemented in the absence of the other fat soluble vitamins notably  D and K. Animal studies have demonstrated that vitamin A both decreases the toxicity of and increases the dietary need for vitamin D and vice versa.205 In addition, concomitant supplementation with vitamin D significantly increased the dose of vitamin A that causes toxicity.206

Multiple studies have shown that vitamin A deficiency increases inflammation and more limited research has shown supplementation decreases inflammation. This appears particularly important for the mucosal barriers. However, the research is complex as inflammation itself appears to decrease blood levels of vitamin A.207

Zinc - Zinc plays a crucial role in the function of essentially all immune cells. Deficiency of this critical element has a profound impact on immune response, increasing susceptibility to a variety of infections.208-212 One of zinc's critical roles in immune function is its role in thymulin production and activity.213

In addition, zinc has specific and well-known antiviral properties.214 Increasing intracellular zinc concentrations in cell culture impairs the replication of a variety of RNA viruses including SARS-CoV-1. Intracellular zinc has been shown to inhibit RNA synthesis by suppressing the SARS-CoV-1 replication and transcription complex.215 In vivo evidence for zinc's antiviral role comes from a Cochrane review that found zinc intake was associated with a significant reduction in the duration of the common cold. Many of the studies showing benefit when taken during the course of an infection were in the form of a zinc lozenge.216 It makes sense to utilize this mode of delivery during the acute infection phase.

Zinc has also been shown to suppress Th17 cell development.217 Interleukin-17 (IL-17) made by Th17 cells has been shown to drive an inflammatory feedback loop via IL-6 induction.218 Zinc dependent transcription factors are involved in the regulation of the gene expression of IL-6 and TNF?.219 The effect of SNPs in genes encoding zinc transporters on blood zinc levels in humans has been examined.220 Older individuals with gain of function IL-6 SNPs have been shown to have a greater need for zinc.221 Zinc supplement in older individuals with gain of function IL-6 SNPs and low zinc were shown to have lower IL-6 and MCP-1 levels upon zinc supplementation.222

Anosmia (loss of smell) and dysgeusia (distorted sense of taste) are commonly being reported in patients at every phase of COVID-19.223 These are also classic symptoms of zinc deficiency. It is too early in the discovery process to determine if this is cause or effect, nonetheless zinc deficiency greatly impairs immune function, especially resistance to viral infections. Notably, inadequate dietary consumption of zinc is found in almost half the older population.224

Vitamin C - Vitamin C is recognized as an essential nutrient in many aspects of the immune system, especially immune cell function of both the innate and adaptive immune responses.225,226 Microbial killing requires vitamin C for chemotaxis, phagocytosis and generation of ROS.227,228 Vitamin C deficiency contributes to decreased immune responsiveness and increased susceptibility to infections. Once infected, the enhanced inflammation and metabolic requirements place a further demand for additional vitamin C.229 Vitamin C supplementation has been shown to both prevent and treat respiratory and systemic infections. The utility of vitamin C and thiamine in sepsis has been reviewed.230

Optimal cell and tissue levels of vitamin C in the plasma saturation range are needed for prophylaxis, while treatment of infections requires significantly higher doses.231,232 In addition, vitamin C's role as an antioxidant is important in protecting the body against the damage from oxidative stress generated during an infection.233,234 Vitamin C also plays an critical role in endothelial stability, supporting nitric oxide generation and vasodilation.  In light of the coagulopathy found in many COVID-19 patients, this role seems highly relevant.235

The CITRIS-ALI study, an RCT published in JAMA in 2019, showed a possible decrease in mortality in 167 patients with sepsis-related ARDS receiving ~15 grams/day of IV vitamin C for four days.236 Recruitment is underway at this writing for an RTC IV vitamin C trial (24g/day) in COVID-19 patients hospitalized with severe pneumonia.237 At Northwell Hospital in New York, there are multiple anecdotal reports of the use of IV vitamin C (1500 mg TID to QID) in COVID-19 patients. Those receiving the IV vitamin C appear to be doing significantly better than those not receiving it.238

A meta-analysis of six controlled trials published in March 2019 demonstrated that an average oral delivery of 2 grams of vitamin C per day shortened length of ICU stay by 8.9%. In three trials in which patients required mechanical ventilation for over 24 hours, vitamin C shortened the duration by 18.2%.239

Quercetin - As discussed above, the antiviral roles of zinc are well documented. However, protection of cells against viral appropriation of cellular metabolism to replicate viral RNA requires adequate intracellular zinc. Ionophores play a critical role in facilitating transport of zinc into cells. The commonly available flavonoid quercetin is a zinc ionophore and has been shown to facilitate transport of zinc across lipid membranes. This is particularly relevant as chloroquine is also a zinc ionophore, which has been postulated as a possible mechanism for its apparent efficacy against SARS-CoV-v2.240,241

Quercetin is also important as one of multiple flavonoids shown in vitro to block the activity of MERS-CoV 3CLpro, a critical enzyme for coronavirus replication. Animal studies are limited at this time but support efficacy.242

In a molecular docking study looking for agents that could bind to the SARS-CoV-2 Viral Spike Protein and thus have potential to inhibit its infectivity, researchers found quercetin to be the fifth most effective.243 However, quercetin has low bioavailability and therefor requires special formulations to achieve clinically effective blood levels. A trial with a phytosomal quercetin formulation has been started in Italy on 660 hospitalized COVID-19 patients (private communication with study PI).

Fish Oil - The role of fish oil in reducing inflammation is long established. However, in an acute care setting, the time scale involved in addressing acute inflammation may preclude the use of fish oil as a strategy for influencing the body's inflammatory equilibrium. Nonetheless, it is worth mentioning the potential role that specialized pro-resolving lipid mediators (SPMs) may play in influencing the biology of risk, in those for whom care is occurring in the Prevention Phase.

SPMs are downstream products of the metabolism of EPA and DHA, the primary active constituents of fish oil. EPA is the precursor for the E series resolvins, and DHA is the precursor for the D series resolvins, neuroprotectins, and maresins.244,245 These lipid mediators play a key role in the resolution phase of the inflammatory process.9

SPMs can inhibit priming and activation of macrophage NLRP3 inflammasome (in vivo and in vitro). SPMs, specifically D2,246 suppressed IL-1? production and secretion in LPS- and ATP-challenged macrophages, and reduced inflammasome assembly and caspase-1 activity. D2 also deactivated the inflammasome in a mouse peritonitis model, as shown by reduced IL-1? release and increased M2 markers of inflammation resolution.

 2. Natural Killer (NK) cell support

Radix astragali (Astragalus) - One of the top prescribed botanicals in TCM preparations for SARS-CoV-1 was Radix astragali, with numerous published clinical trials demonstrating significant efficacy for both prevention and treatment. In SARS-CoV-2, astragalus continues to be the most common botanical in TCM prevention formulas prescribed in China.247

Andrographis paniculata (Andrographis) - The antiviral properties of andrographis have been proposed as leads for pharmaceuticals in the antiviral drug discovery literature.248-251 Andrographis has been shown in human randomized controlled trials to be effective in upper respiratory tract infection252,253 and pharyngotonsillitis.254 Andrographis has been shown to promote natural killer cell activity255,256 and also reduce the levels of inflammatory cytokines.257

Ganoderma lucidum (Reishi mushroom) - Ganoderma has been used in traditional Chinese medicine (TCM) for thousands of years. The antiviral properties of ganoderma have been studied in dengue,258,259 HIV,260 HPV,261 enterovirus71,262 and herpes.263 Reishi activates NK cells264-268 and Th1 cells269,270 and downregulates inflammatory cytokines in human alveolar epithelial cells.271,272

3. Th1 cell support

Berberine - containing Botanical Medicines (Hyrastis canadensis, Coptidis Chinensis) - Berberine has been shown to have activity across a broad range of viruses.273-280 Berberine has activity against RSV via upregulation of type 1 interferons.281 Type 1 interferons are key activators of NK cells and play a central role in antiviral immunity.282,283 The anti-inflammatory,284-286 cardioprotective,285,287 and antifungal effects of berberine have also been reviewed.288 One mechanism by which berberine downregulates inflammation is through activation of AMP kinase (AMPK).289 AMPK is a known activator of SIRT2,290 a known inhibitor of NLRP3 inflammasome assembly.23 Other mechanisms of berberine inhibition of NLRP3 have also been described.291-293 Berberine-induced AMPK inhibits IL-6-induced inflammation in human liver cells by inhibiting STAT3, the signal transduction factor required for Th17 cell differentiation.294 Berberine promotes the Th1 cytokines IL-12 and IFN? and inhibits the Th2 cytokine IL-4.295-297

Berberine also has potential advantages in impacting clotting. Hypoxia inducible factor 1 alpha (HIF1?) has been described as a promoter of thrombosis.298-300 As the name implies, HIF1? is upregulated by tissue hypoxia. With poor oxygenation, higher HIF1? levels will drive more thrombus formation. As described before, neutrophil NETs offer an additional base material for clot formation.60 The combination of these factors may be a driving force in the extensive pulmonary microvascular damage seen in severe manifestations of COVID-19. Berberine has been shown to downregulate HIF1?.301-305

In a human trial with 130 acute coronary syndrome subjects receiving percutaneous coronary intervention, those receiving 300 mg of berberine TID for 30 days had significant reductions in matrix metalloproteinase (MMP)-9, intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, C-reactive protein, IL-6 and monocyte chemoattractant protein-1 (MCP-1), all of which are inflammatory signaling molecules.306

Goldenseal is often used because its high concentration of berberine. In a study examining the inhibition of influenza A by berberine, goldenseal at higher dosages was found to be effective at inhibiting both growth of influenza A and production of TNF? and PGE2.307

Baicalin - containing Botanical Medicines (Scutellariae baicalensis (SB) and other Scutellaria spp.) - The high infectivity rate of SARS-CoV-2 separates it from the genetically similar SARS-CoV-1. Preprint research suggests that one difference might lie in a unique furin-like cleavage site on the SARS-CoV-2 Spike protein that is absent in SARS-CoV-1.308 Dengue virus also infects human cells via furin cleavage, and could be inhibited in vitro and in vivo by application of the flavonoid luteolin.309

Evidence for antiviral, antioxidant, and anti-inflammatory effects of SB has been reviewed.310,311 The ability of SB to downregulate Th17 cell differentiation , the major source of IL-17 that induces macrophage IL-6 production , has been reviewed.312 Compounds isolated from SB have been shown to have antiviral and Nrf2-promoting antioxidant properties.313 SB has shown utility in downregulation of NLRP3 inflammasomes,314,315 antimycobacterial and anti-inflammatory effects in macrophage infection,316 and anti-H1N1 activity in vitro and in vivo through induction of IFN-? producing cells.317 Activity against H1N1 and H3N2 infected cells has been show to be associated with upregulation of type 1 interferons.318

In children with acute lymphocytic leukemia, administration of SB extract yielded increased production of IFN? in peripheral blood lymphocytes (PBLs), and reduced TNF? and IL-10 production in bone marrow cells (BMC), in all patients.319 The increase in immune surveillance (increased IFN?) and downregulation of inflammation (reduced TNF?) constitute a potentially useful dual effect. Other phytochemicals similar to SB have been identified that block the entry of SARS-CoV into host cells.320

Glycyrrhiza glabra (Licorice root) - Glycyrrhiza glabra, common name licorice root, has a long history of use in Western herbal medicine for viral infections and in traditional Chinese medicine (TCM) as a key ingredient for pandemic formulas. It was a component in TCM formulas for SARS-CoV-1 prevention and treatment. Along with astragalus, it is the most frequently used botanical in TCM formulas for SARS-CoV-2 prevention in China.321 Multiple clinical trials have demonstrated its effectiveness as a part of TCM formulas for CoV-1 and H1N1.322 Numerous in-vitro studies have shown the major active constituent of licorice, glycyrrhizin, to be effective against SARS-CoV-1.322 The Th1 promoting properties of licorice may contribute to its antiviral action and have been reviewed.323

A 2003 study published in Lancet looking at two clinical isolates of coronavirus from patients with SARS-CoV-1 identified glycyrrhizin to be the most active component of licorice in inhibiting viral replication as compared to ribavirin, 6-azauridine, pyrazofurin, and mycophenolic acid.324

A preprint molecular docking study suggests that the major active constituent, glycyrrhizin, can bind the ACE2 receptor, and therefore may have anti-SARS-CoV-2 activity.325

Licorice is considered a botanical of low toxic potential and has been safely used in Western and Eastern herbal medicin for millennia. However, excessive use can exert an aldosterone-like affect resulting in potassium wasting. Prescribing glycyrrhizin in individuals on potassium wasting medications may result in hypokalemia.326 It's also important to note that SARS-CoV-2 itself has been associated with potassium wasting,327 as is hydroxychloroquine, a drug gaining some renown as a potential COVID19 therapeutic, especially early in the disease process.328 Clinical considerations for patients with an increased risk for cardiac arrhythmias, either secondary to acquired conditions or co-morbidities or consequent to inherited syndromes, have been reviewed.329 Thus, while glycyrrhizin may be a very important COVID19 intervention, serum potassium should be monitored to avoid hypokalemia in vulnerable individuals.

Note that while DGL has substantial clinical research for such conditions as gastric ulcers, this form is not appropriate for COVID-19 as it is deglycyrrhizinated, i.e., the antiviral constituent has been removed.

Echinacea spp. - Extracts of various species of echinacea have been used traditionally in North America for many years and are currently popular for the treatment of many types of upper respiratory infections. Recent studies have supported its use by demonstrating that echinacea extracts possess potent pleomorphic antiviral activities. Direct viricidal activity has been demonstrated particularly against membrane containing viruses including coronaviruses by targeting membrane components, capsid proteins, and virus replication. In addition, reversal of the pro-inflammatory response of epithelial cells to viral infection, and reduction of excessive mucin secretion has also been observed.330,331

Of possible particular utility in COVID-19 is a species of echinacea with a long history of use in Western herbal medicine: Echinacea angustifolia. Also known as narrow-leaved purple coneflower, this medicinal herb is native to North America. A particular standardized extract of echinacea was shown to upregulate IL-2 and IL-8 and downregulate TNF? and IL-6 gene expression.332 An uncontrolled pilot study of this preparation in 36 adults with existing respiratory disorders (chronic bronchitis, respiratory insufficiency, or intrinsic asthma) found improved response to influenza vaccination and a substantial, statistically significant increase in IgG.333

Variation in extractions methods, errors in identification, and inconsistent choices in part of plant used present challenges in the clinical choice of echinacea products. Research on a particular extract cannot be reliably extrapolated to other products.

Th2 Dominance Inhibition - Understanding the complex dynamics of T cell polarization patterning has gone far beyond Mossman's original Th1/Th2 dichotomy.334 There are currently seven known maturation fates of naïve T cells, and immunologists no longer think of Th1 as inflammatory and Th2 as anti-inflammatory. In patients whose baseline function likely involves Th2 dominance, indicated by asthma, chronic sinusitis, allergies, or other known Th2-dominant disease processes, or in patients for whom there are other concerns about the prospect of a loss of adequate Th1 response early in the infection phase of illness, it may be useful to consider downregulating an overly exuberant Th2 response.

Perilla spp. - Perilla has been shown to downregulate Th2 dominance-based processes like allergic airway inflammation, seasonal allergic rhinoconjunctivitis, and asthma.335,336 Mechanistic studies suggest this effect is mediated by downregulation of Th2 effector cytokines, including most importantly (IL-4), the cytokine driving Th2-biased autocrine responses. Perilla has also been shown to inhibit platelet aggregation and thrombus formation.337,338 Dietary supplementation with perilla seed oil in patients with asthma suppressed the generation of leukotriene (LT) C4.339

Radix astragali (Astragalus) - Astragalus has substantial Th2 inhibiting properties. As with perilla, astragalus significantly decreased intensity of Th2 dominance-based disease processes like rhinorrhea.340 Mechanistic studies have shown that astragalus downregulates Th2 cytokines and lowers the ratio of GATA3 (Th2 cell transcription factor) to Tbet (Th1 cell transcription factor).341-343 Astragalus also upregulates the formation of NK cells in peripheral blood mononuclear cells (PBMCs) from SLE patients.344

4. Anti-Inflammatory Support

Inhibition of the NLRP3 inflammasome and NFkB are central to this task.

Potassium - Maintaining blood potassium levels is important, to prevent potassium cellular efflux, which upregulates inflammasome assembly.42

COVID-19 drug therapy guidance published on April 8, 2020, from the American Heart Association, the American College of Cardiology, and the Heart Rhythm Society states that hypokalemia should be corrected to >4.0 mEq/L and hypomagnesemia corrected to >2.0 mg/dL.345

Curcuma longa (Tumeric) - Curcuminoids are long used turmeric-derived compounds with well-documented pleotropic effects, including antiviral and anti-inflammatory activity.346,347

As has been discussed, the aggressive virulence of SARS-CoV-2 may be driven in part by upregulation of NLRP3 leading to production of IL-1?, IL-18 and pyroptotic cell death.348

Curcuminoids have been shown to specifically inhibit caspase-1 activation and IL-1? secretion through suppressing LPS priming and NLRP3 activation.349

Regarding activity specific to SARS-CoV-2, recent prepublication molecular docking data suggest that the curcuminoids demethyoxycurcumin and curcumin have viral replication inhibition potential against the main protease (Mpro) identified as likely involved in viral maturation and spread. Note that a number of other flavonoids demonstrated inhibition potential in the docking study, with the strongest and best potential SARS-CoV-2 Mpro inhibitors being: kaempferol, quercetin, luteolin-7-glucoside, demethoxycurcumin, naringenin, apigenin-7-glucoside, oleuropein, curcumin, catechin, and epicatechin-gallate.350

In another molecular docking study, curcumin showed effective inhibition of SARS-Cov-2 Spike viral glycoprotein binding to ACE2 receptor. While these data are clearly preliminary, the findings suggest the potential of curcumin to halt viral entry into host cells. Other effective flavonoids included hesperidin, with the highest binding affinity.351

Bromelain - Many studies have documented efficacy of bromelain in reducing inflammation and inflammatory diseases. Clinical benefit has been shown in injuries, infections, respiratory tract diseases, arthritis, inflammatory bowel disease, etc. Of particular importance here is its documented ability to decrease tissue edema and inflammation.

Several studies have shown that bromelain is effective in respiratory conditions such as asthma, bronchitis, and sinusitis that are characterized by increased mucus production and inflammation. Spirometry before and after bromelain treatment demonstrated increased FEV1 and vital capacity, which were suggested by the researchers to be a result of bromelain's mucolytic activity.352,353

Of particular interest here is the limited research showing that bromelain decreases cytokines. A placebo-controlled randomized clinical trial found that high-dose oral bromelain showed immunomodulation of both Th1- and Th2- cytokines.354

Resveratrol - Constituents of resveratrol have been shown to reduce inflammation via several mechanisms including downregulation of IL-6 and TNF? and promotion of Sirtuins.355-358 Crucial to the utility of resveratrol is its ability to inhibit the accumulation of acetylated ?-tubulin caused by mitochondrial damage in macrophages stimulated by NLRP3-inflammasome induction. Inflammasome assembly is strongly induced by acetylated ?-tubulin. Resveratrol upregulates SIRT2, a known deacetylator of ?-tubulin.359-361 The utility of resveratrol has been studied in SARS-CoV-1.362 Resveratrol has been shown to protect lung epithelia against the effects of cigarette smoke by upregulating Nrf2 to promote GSH.363

The utility of resveratrol has been studied in a wide range of diseases including cardiovascular364 and metabolic inflammatory processes.365

Quercetin - See the quercetin discussion above.

Melatonin - See the melatonin discussion above.

Boswellia serrata (Boswellia) - Via a variety of mechanisms, boswellic acid (BA), an active constituent in Boswellia serrata, exerts a number of anti-inflammatory effects. BA was shown to potently inhibit TGF? induced pulmonary fibrosis and 5-lipoxygenase in an animal model.366 BA has also been shown to significantly inhibit cyclooxygenase, NFKB signaling and TNF?.367,368

Sulforaphane - Sulforaphane is a well-studied anti-inflammatory phytochemical found in cruciferous vegetables that also inhibits NLRP3 inflammasome biology.369,370 Sulforaphane activates the antioxidant Nrf2 pathway and drives significant anti-fibrotic activity benefit in both TGF? treated cell lines, and induced fibrosis in animal models.371 Sulforaphane also upregulates GSH levels.372,373

It is noteworthy that curcumin, resveratrol, quercetin, and berberine have all been shown to promote AMPK.374 AMPK is a promoter of SIRT2, also known to inhibit NLRP3 inflammasome assembly.23


 5. Anti-Oxidant Support

Patient GSH status can be supported with oral GSH (liposomal forms appear to offer better absorption), NAC, vitamin E, and selenium. In addition, GSH can be delivered by nebulizer or by IV. It may be appropriate to give both NAC and GSH, in service of supporting GSH status. When available, lab testing can support the clinician's monitoring of GSH levels.

NAC and GSH - Oral and Nebulized Delivery

Nebulized NAC and reduced GSH have a long history of clinical use by natural/ integrative/ functional/ holistic doctors for the treatment of COPD and other chronic inflammatory lung conditions. While there is substantial research support for the value of oral NAC and oral GSH in respiratory illnesses, the research to date on the nebulized delivery is limited but encouraging.

NAC-oral, IV and nebulized-has considerable research support for improving respiratory tract immunity, normalization of inflammation, helping reduce excessive mucous secretion and functioning as a mucolytic. A recent review well summarized its value in respiratory diseases:

Biological and pharmacological effects of NAC include improvement in rheological properties of mucus, reduction of excess mucin production, restoration of mucociliary clearance and production of sIgA, suppression of excess production of IgE and IgG4, destruction of biofilms and inhibition of their formation, suppression of adhesion of pathogenic bacteria to epithelial cells, antioxidant activity, regulation of the production of pro-inflammatory and profibrotic cytokines.375

While nebulized forms are likely more effective, oral NAC at 600 mg bid was shown in in a controlled study of patients with COPD to significantly improved PaO2, PaCO2, wheezing, and dyspnea and decrease the need for nasal oxygen support.376

While most studies support this intervention, a clinical study on mechanically ventilated patients showed that while NAC was more effective than saline in decreasing mean secretion density the results were not statistically significant (P = .087), likely due to a small sample size (20 patients in each arm). However, despite small sample size, NAC was significantly effective at increasing O2 saturation.377

A randomized, controlled study of IV NAC (50 mg/kg/day for three days) for 27 ICU patients with ALI/ARD demonstrated statistically significant improvement in oxygenation and decreased mortality.378

Normally, nebulized GSH would be recommended for respiratory inflammation. However, the high level of mucous secretion in COVID-19 could impair its ability to penetrate deeply enough into the lungs. Therefore, the authors recommend IV GSH, to protect both the lungs and also the heart from the damaging inflammation.

While there are a considerable number of controlled clinical studies on the various forms of NAC, there is a surprising dearth of such studies on IV GSH as an independent therapy. Virtually all existing studies examine the use of IV GSH in conjunction with drugs, especially chemotherapy agents. There are several studies showing modest benefit in Parkinson's disease, but virtually no other conditions we could find in PubMed.379

The research is clear that inhaled GSH substantially increases blood levels. A few controlled studies have shown modest benefit from inhaled GSH in cystic fibrosis and asthma.380,381


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