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ySARS-CoV-2 electromicrograph. Credit NIAID-RML

COVID-19 pandemic: Measures to be taken for its prevention and treatment

The agnostic’s half-truth busted — An Integrative approach

Disclosures:

No funding has been received and there is no conflict of interests

Outline

Abstract

Characteristics of COVID19: Know thy enemy

Clinical & Epidemiologic aspect

The virus-host interaction

Respiratory distress

ARDS pathogenesis

Gender difference

Prophylactic measures: A strategy for the reduction of risk

Establishing a strong primary care system

General prophylaxis

Specific prophylaxis

Overview of therapeutic measures

The prevailing treatment

Other treatment options

Immunostimulatory herbal medicines

Treatment considerations for the severely ill

1. Glucocorticoids (GCs)

2. Anti-sera

3. Measures to counter cell-free hemoglobin (CFH) effects

4. Chloroquine & Azithromycin

5. Colchicine

6. Estrogens

7. Spironolactone & other ACE2-related agents

8. Phytocannabinoids (CBD & THC)

9. Proposed drug combinations, based on computational network analysis

Conclusions

Summary

Conflict of interest

Bibliography

Abstract

Purpose: To assess the COVID19 pandemic from an integrative perspective. Generalities: SARS-CoV-2 is a novel coronavirus of still not fully traceable origin that took the World unawares. It clinically resembles usual flu-like syndromes, with a benign or even asymptomatic course. The elderly and people with certain pre-existing morbid conditions tend to become severely ill and even die. The unfavorable course is usually introduced with generalized immune dysregulation accompanied by difficulty breathing, rapidly evolving into acute respiratory distress syndrome, possibly progressing into multiple systems failure and death. The immune dysregulation is ushered by a sudden increase of IL-1β or IL-6, usually between days 5 and 7 of the disease. The common element of comorbidities underlying unfavorable outcomes is a pre-existing low-grade inflammatory state. Based on the above, the prevailing opinion that “we do not know enough to fight it” seems more as an agnostic’s postulation than a scientifically justified premise.

Multi-level strategy: We present a strategy for reduction of risk, including public health measures, and measures for improving general health; the pros and cons of specific prophylactic measures, including vitamins, minerals and hormones, and popular phytotherapeutics are discussed, along with possible measures for the severely ill, including conventional and novel uses of old drugs.

The outlook: Given our genome, proteome, etc, few new drugs with manageable adverse effects are possible. Intense research for expensive drugs is an established trend, but modern medicine should also seek to repurpose existing inexpensive substances like melatonin, chloroquine, acetaminophene, etc, and use previously miscategorized multi-potent substances, like cannabinoids, in clinical trials.

Introduction

“If you know the enemy and know yourself, you need not fear the result of a hundred battles.”

Sun-Tzu: “The art of war”. The Beijing Military Museum
Sun-Tzu: “The art of war”. The Beijing Military Museum
Sun-Tzu, the legendary author or editor of “The art of war”. This portrait is from the Beijing Military Museum

Concerning the present pandemic, the prevailing opinion is that “we do not know enough to fight it”. What is really meant by this, is that we do not fully understand some specifics of the infection and its epidemiology, and we do not have a vaccine and a specific anti-viral drug. But this is an agnostic’s postulation because, as will be proven below, we do know a lot of things in detail, like general epidemiology, virology, immunology, plenty of pharmacology, pathophysiology and so on, more than enough to fight the novel pandemic intelligently. An intelligent way to address this worldwide problem should optimize restrictive measures so that the death toll, the burden to the health system, and economic consequences be minimized; an optimization strategy will be presented here, partially applicable immediately and partially for future challenges.

The novel virus SARS-CoV-2 is, no doubt, highly virulent and with a rather long incubation period, presently estimated up to 14 (or maybe more) days, usually five. These two factors, combined with globalization and the naivety of the so-called “herd” to the virus, set the stage for the swift evolution of the prevalence of COVID19 from scarce to sporadic, to epidemic, to pandemic. The classical approach to such infectious diseases is either extensive vaccination with the intent to establish acquired immunity or some sort of drug therapy that will either kill the virus or strengthen innate immunity of the “herd”, or at least, the individual; any combination of the above is also in order. Letting the pandemic alone would probably be the fastest way to the establishment of “herd” immunity but with a high risk of overwhelming the health system and the unbearably high number of deaths. The course to be chosen by governments is largely a matter of availability of medicinal resources, prevailing public sentiment, and the choice of when governments would prefer to face the political consequences entailed; sooner, by letting the pandemic evolve quasi-freely, or later, by taking measures leading to an economic recession along with severe social consequences.

An integrative approach to COVID19 (or any other challenge of the like) would focus primarily on prevention, by strengthening innate immunity, by managing public health measures like social distancing, and by attempting to alter the course of the disease towards a favorable outcome, should the disease be more aggressive for some individuals than the immune system could possibly handle by itself. The lay public has expressed a high level of interest in integrative strategies for two reasons: a. The lay public believes that there is a paucity of drugs able to fight the infection, and, of course, no vaccine; addressing the infection without bias for or against some drug categories looks more optimistic to them, and b. the shifting of the therapeutic paradigm away from the prevalent one, which is “just kill the intruder”. Besides, as stated by Martinez (2020), “Therapeutics that target the coronavirus alone might not be able to reverse highly pathogenic infections”, and suggests that one should also look into the host reaction. The problem is that most integrative measures are not evidence-based; clinicians and the public accept them based on pre-existing knowledge based on traditional medicine, and pre-clinical evidence. The value of the latter is considered as low-quality evidence. For this reason integrative practitioners should restrict themselves to recommending only substances known as generally safe.

In difficult situations like this one, one should feel free to improvise to some extent. For instance, unavailability of data could be provisionally remedied by assuming that the SARS-CoV-2 will have some similarity to the well-studied cousin of his, SARS-CoV and other members of the corona family; in such a case we could probably apply whatever measure worked previously and try to prove if they also work in the COVID19 case. In this review, oftentimes data will be mentioned that are not directly related to SARS-CoV-2, in the sense that we could theoretically capitalize on them, since biochemical pathways, physiology and pathophysiology apply generally until proven otherwise. It goes without saying that measures already prescribed by governmental institutions, like social distancing, hand washing, etc, should be observed in the first place; a proviso should be added concerning aggressive social distancing, to the extent of social shut-down: The victims of it may surpass the ones from COVID19 and they will be mainly from the socially active stratum of society, as opposed to the ill and the debilitated (Ioannidis, 2017).

Characteristics of COVID19

Clinical and Epidemiologic

The SARS-CoV-2 infection produces mainly flu-like symptoms, generally of mild to moderate intensity. The triad of fever, tiredness and dry cough is strongly suggestive of COVID19, especially if one has not been observing social distancing. Recent travel is not any more of use as a diagnostic criterion because there are plenty of non-traceable cases in the community. Other common symptoms are reduced sense of smell, sore throat, runny nose alternating with nasal congestion, back and limb aches; diarrhea is pretty uncommon. It takes usually 5 to 6 days from infection to clinical manifestation but the latent period could be up to 14 days or even longer. Children are frequently asymptomatic but, despite that, they are strong transmitters of the disease.

The virus-host inteaction

Three strains of coronavirus, including SARS-COV-2 have protein spikes on their surface that serve as “siege rams” to enter the cells. Said protein spikes are activated in the presence of furin, a ubiquitous endopeptidase found in many human tissues and plasma, particularly in the lungs, which explains the predilection of SARS-CoV-2 for the lung. Furin breaks down a portion of the protein chain of the spike (S1/S2 cleavage), and so the latter is activated. The cleaved (primed) spike readily connects to the membrane receptors of the angiotensin 2-converting enzyme (ACE2R), which are also endopeptidases, that convert angiotensin II (AT-II) into angiotensin 1,7 (AT-1,7), thereby protecting from AT1 receptor activation and inducing the anti-hypertensive effects of AT-1,7. The ability of ACE2Rs to connect to the cleaved spikes of the virus makes them sockets, points of attachment, and gateways for SARS-type coronaviruses, including SARS-COV-2.

Schematic representation of SARS-CoV-2
Schematic representation of SARS-CoV-2
Credit:

The entry of SARS-CoV2-RNA into the cells through membrane fusion markedly down-regulates ACE2Rs. The unopposed activation of the ACE → Angiotensin II→ AT1R axis induces vasoconstriction, thrombosis, and inflammation in the lung. Verdecchia et al (2020) mention that “clinical reports of patients infected with SARS-CoV-2 show that several features associated with infection and severity of the disease (i.e., older age, hypertension, diabetes, cardiovascular disease) share a variable degree of ACE2 deficiency”. They go on suggesting that ACE2R down-regulation induced by viral invasion may be especially detrimental in people with baseline ACE2R deficiency associated with the above conditions, in the same way that the same conditions elicit inflammasome priming (see ARDS pathogenesis, below). “The additional ACE2 deficiency after viral invasion might amplify the dysregulation between the ‘adverse’ ACE→Angiotensin II→AT1 receptor axis and the ‘protective’ ACE2→Angiotensin1–7→Mas receptor axis” (Verdecchia et al, 2020). This mechanism may contribute significantly to ARDS pathogenesis in cases infected with SARS-CoV-2.

Given the central role of furin and the ACE2R in the infectious process, it is possible that either or both these endopeptidases be promising targets of pharmaceutical manipulation (see “Spironolactone and other ACE2-related drugs”, below).

Furin normally activates the inactive pro-forms of various proteins (eg pro-parathormone, pre-factor v. Willebrand, etc.), so it is essential for life. But it is also a necessary factor in the composition of the envelope of the infamous HIV (AIDS) virus, influenza viruses, dengue fever, Ebola, and SARS-COV-2 (COVID-19) when they have already infected the human cells and follow their biological cycle. High plasma furin levels have been associated with a pronounced dysmetabolic phenotype, auto-immune diseases, and premature mortality (Ranta et al, 2015, Fernandez et al, 2018); low levels have been associated with systemic hypertension (Yan He et al, 2019).

Apart from the main mechanism of intrusion to the cell, the spike-ACE2R interaction, the corona of SARS-COV-2 virus contains additional means of cell invasion: The corona possesses secondary spikes, composed of hemagglutinin esterase (HE), a glycoprotein, which has the following types of infection promoting properties:

· It binds to glycolipids and glycoproteins of the membrane, thus increasing the chance of initial anchorage of the virus.

· It causes fusion of the cell membrane and the viral envelope, a prerequisite for the “injection” of the RNA of the virus into the cytoplasm.

· It hydrolyzes protein of the cell membrane, thus facilitating the spread of the virus to healthy cells.

Respiratory distress

The course of pathological events of COVID19 is still not fully understood, but it is clear that people who become severely affected die of acute respiratory distress syndrome (ARDS) and eventually from the ensuing multiple systems insufficiency. ARDS is characterized by the acute onset of pulmonary non-cardiogenic edema, pulmonary infiltrates and reduced lung compliance, leading to refractory hypoxemia (Umbrello et al, 2017). The key here is the inflammatory process going out of control. In some cases of COVID-19, patients undergo an acute immune dysregulation with deterioration into ARDS even before any noticeable deterioration of the overall state of the patient. Most patients suffer from immune dysregulation triggered by monocyte hyper-activation, excessive release of IL-6 and profound lymphopenia, mainly affecting CD4 and NK-cell classes of lymphocytes. The rise of IL-6 and/or IL-1β (the cytokine storm) immediately precedes the immune dysregulation (Giamarellos-Bourboulis et al, 2020); these two interleukins could, therefore, be used as a monitor of impending clinical worsening. The need for a personalized, cytokine-based diagnosis has been brought forward almost simultaneously by Rahmati & Moosavi (2020).

COVID19 lung CT: Typical peripheral ground-glass appearance
COVID19 lung CT: Typical peripheral ground-glass appearance
COVID19 CT: Typical peripheral ground glass appearance

ARDS pathogenesis

Irrespective of etiology, the pathogenesis of ARDS is complex and involves an unbalanced production of pro-inflammatory molecules that creates overwhelming inflammation locally and/or systemically (Huang et al., 2019). Evidence exists that the development and course of ARDS seem to be related to Toll-Like receptor (TLR) and NOD-like receptor (NLR) signaling pathways (Han & Mallampalli, 2015). The most important of the latter is the NLRP because it is a central component of macrophage inflammasomes, which are cytosolic protein complexes of the innate immune system; their activation and assembly promote proteolytic cleavage, maturation and secretion of IL-1β and IL-18. NLRP is activated by pore-forming bodies (toxins, virions, etc that can create pores on the mammalian cellular membrane) when conditions are suitably primed (Franchi et al, 2012, Kelley et al, 2019).

PAMPs/DAMPs-inflammasome activation
PAMPs/DAMPs-inflammasome activation
PAMPs/DAMPs inflammasome activation (Credit: Bo-Zong Shao et al, 2015, DOI:10.3389/fphar.2015.00262. Activation of inflammasomes (priming) prior to SARS-CoV-2 infection is the common element in cases that will develop a “cytokine storm”. This is common in the elderly, the obese, the diabetic, the hypertensive etc.

Understanding NLRP3-inflammasome priming may be crucial for explaining why some comorbidities may turn a usually simple flu-like syndrome into a catastrophe; transcriptional upregulation of NLRP3 and pro-IL-1β expression is required, together with post-translational modification of NLRP3 itself. Obesity, diabetes, hypertension, cancer, old age, and other chronic inflammatory states prime the NLRP3 inflammasome, and these constitute serious predisposing factors for massive inflammasome activation in COVID19 (Richardson et al., 2020), obviously, because the viral infection finds in some cases inflammasomes in a pre-primed state; the virus exacerbates an already lit-up, ready-to-go, low-grade inflammation. Once assembled, inflammasomes of macrophages and T-helper cells (Th1-lymphocytes) generate active IL-1β, IL-18 and caspase-1. Inflammasome-regulated cytokines are associated with worse outcomes in ARDS subjects (Dolinay et al., 2012). Mitochondrial debris, now acting as mDAMPs (mitochondrial Damage Associated Molecular Patterns) released into the circulation after cellular damage also promotes inflammation, and especially the so-called SIRS or Systematic Inflammatory Response Syndrome ((Zhang et al, 2010). Persistence of systemic inflammation has been established as the cause of non-resolving ARDS; in early childhood, cases can rarely present as a non-localizing inflammatory condition, the so-called Kawasaki syndrome but the connection to SARS-CoV-2 is still nebulous. Systemic inflammation-associated acquired glucocorticoid (GC) resistance is one decisive factor concerning the persistence of ARDS; another is the ratio CD4+/CD8+: If the ratio stays high for too long, then the probability of persistent ARDS increases; if it stays too low, the virulence of the virus will be higher. It should be noted that the production of autoantibodies presents another menace in severe ARDS cases; they are rapidly produced and are not curbed by GCs. The rapid induction of autoantibodies in ARDS and severe sepsis suggests that tissue destruction secondary to uncontrolled systemic inflammation mediates the failure of recognition of own proteins (Burbelo et al., 2010).

Gender differences in COVID19 morbidity and mortality

The SARS-CoV-2 virus affects equally men and women but men are more at risk for a worse course, outcome, and even death, independent of age (Jin et al, 2020).

Male/Female death rates from COVID19 by country
Male/Female death rates from COVID19 by country
Male/Female death rates from COVID19 by country. Credit: F. Uzun, TRT-World

Sixty percent of the hospitalized were men; mortality rates were higher for men compared to women for every 10-year age step above the age of 20 (Richardson et al, 2020); overall, almost 50% more affected men die than women (Suba, 2020).

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Death rate by age in COVID19. Credit: Deutsche Welle

Governmental policies and public health institutions have not assessed gender differences in coping with epidemics. This attitude was no different during the present pandemic (Wenham et al, 2020), although the question “Why men do worse than women?” is a rather common one (di Stadio et al, A 2020); the present author feels that an attempt to provide some answers is justified; we should at least have a quick peek into the literature, without expectations for getting explicit answers concerning COVID19. Non-biological differences, like the differential prevalence of smoking, line of profession, etc, will not be considered here. The following tables, adapted from Klein & Flanagan (2016), offers an overview of gender-related differences in the innate and adaptive components of the immune system.

Sex differences in the innate immune system (Klein & Flanagan 2016)
Sex differences in the innate immune system (Klein & Flanagan 2016)
Sex differences in the innate immune system (modified from Klein & Flanagan 2016)
Sex differences in the innate immune system (Klein & Flanagan 2016)
Sex differences in the innate immune system (Klein & Flanagan 2016)
Sex differences in the adaptive immune system (modified from Klein & Flanagan 2016)

One will observe at a glance that females are privileged immunity-wise compared to men and that their T-helper cell balance is Th2-biased, while it is Th1-biased in men. This particular difference makes men more inclined to produce a cytokine storm with IL-1β and IL-6 predominance, IL-1β being also one of the primers of inflammasomes, especially if one of the usual co-morbidities exists (obesity, diabetes, cancer, etc). Besides, B-cells and antibody production have an advantage in women, meaning that they have the opportunity to adaptively fight the virus more quickly and strongly than men. Not mentioned in the table is the advantageous expression of interferon-alpha (IFN-α) in infected women, leading to a brisk initial response that limits the infection of surrounding cells by the virus (Jaillon et al, 2019).

One of the consequences of Th1/Th2 differential bias is manifest as macrophages polarization: Classical M1 activation in response to interferon-gamma (IFN-γ) and LPSs or alternative M2 activation driven by IL-4 or IL-13. The excessive presence of M1 macrophages in males may cause damage to the host while M2-polarized macrophages are protective against infection-induced inflammation like myocarditis, suggesting a role for macrophage polarization in defining the sex-related susceptibility to viral myocarditis (Jaillon et al, 2019), especially in patients with a compromised heart (Jaillon et al, 2019). For all these reasons estrogens have been proposed as a means to treat COVID19-induced ARDS (Suba, 2020) (see below).

Sex hormones are of course very important in immune regulation effected through relevant receptors that immune cells have, thereby being able to directly respond to the presence, absence, or changes in the concentrations of sex hormones. Generally, testosterone and progesterone are immunosuppressive, e. g. on cytokine production and lymphocyte proliferation and sepsis. Estradiol has biphasic effects: at low concentrations it can be pro-inflammatory, whereas at high concentrations can be anti-inflammatory. Estradiol and progesterone can delay the apoptosis of neutrophils (Klein & Flanagan 2016, Jaillon et al, 2019).

AIDS/HIV1 is another coronavirus infection for which we have extensive clinical and laboratory data that could be probably extrapolated with caution to COVID19. Untreated women with AIDS/HIV1 had significantly less circulating viral RNA than men and greater activation of CD8+ T-cells in the short and medium run. IFN-α production in response to HIV1-encoded TLR7 ligands was significantly greater in women than men, and the ensuing secondary activation of CD8+ T-cells was also stronger. The proposed mechanism of the aforementioned was the up-regulation of the interferon regulatory factor 5 (IRF5) gene by estrogens (Jaillon et al, 2019).

Sex chromosomes are also important determinants of sex differential immune responses, beyond sex hormones that were once thought to be the sole regulators of gender peculiarities. Gene-silencing is the chromosomal aspect of the female “immune system supremacy”; concerning immunity, the gene silencing process would be a neutral factor, if the X chromosome were not loaded with immunity relevant genes, and if no gene could evade the process. As a matter of fact, specific genes systematically evade silencing, and others evade it randomly. A whopping 25% of X genes escape silencing in humans, thereby having the opportunity to amplified expression; it is a matter of plain arithmetic that females have higher numbers of escaped copies than males, as they normally possess two X chromosomes. A significant number of escapee genes are connected with the expression and/or regulation of important components of the immune system, like TLRs, IL-receptors, kinases, transcription factors, etc, which thus have the opportunity for enhanced expression in females, compared to their male counterparts, who normally possess only one X chromosome (Klein & Flanagan 2016, Dance, 2020).

Besides the phenomenon of gene silencing, gender bias of the immune system involves non-coding strands of RNA, which come in a short and a long variation. We have briefly referred to the short ones earlier (miRNAs), in the context of glucocorticoid resistant ARDS. The long variation is called long non-coding RNAs (lncRNAs). Neither variation translates into proteins. miRNAs are emerging as regulatory molecules of immunity, and there is indeed a gross imbalance in their production in the two genders; women have the potential of producing 40 times more types than men; their expression may be under sex hormone and X-linked gene control, and they may express more due to the phenomenon of incomplete gene silencing of the double X chromosome. miRNAs tend to induce autoimmune disease in women, as mentioned earlier, they afford resistance to glucocorticoids. In conclusion, miRNAs may be the only negative factor in females, concerning immunity, but they can be tamed with cannabinoids (Sharma & Eghbali, 2014, Klein & Flanagan 2016, Umbrello et al, 2017, Juknat et al, 2019).

The lncRNAs are emerging regulators of immunological processes, including transcrip­tional regulation of innate and adaptive immunity in a manner that is sex-­differential, with a female predominance. Following activation of the innate response, we commonly see rapid induction of these lncRNAs and this is often mediated via the pro-inflammatory NF-κB (Hadjicharalambous & Lindsay, 2019). Their role in the inflammatory process is complex, including innate and adaptive response, and host-virus interaction (Zhang & Cao, 2016) and needs a lot more research.

Prophylactic measures — A strategy for reduction of risk

Establishing a strong primary care system

Generalities

Important aspects of the present pandemic are the following:

· It is novel: We do not know its virulence, its real mortality rate and its exact epidemiological and immunological characteristics. We do not even have enough resources to test the population and map the prevalence of the disease; the tests we have are of questionable sensitivity and specificity.

· There is no known curative treatment and no prevention through vaccination.

· Right from the beginning it has become obvious that the elderly and compromised were the ones that would suffer severe complications and eventually death, compared to the young and the healthy.

COVID19: Death-rates by co-morbidity
COVID19: Death-rates by co-morbidity
Co-morbidities and their impact on the death-toll of COVID19. Credit: Deutsche Welle

The only dependable and meaningful preventive measure is social distancing and this is what most governments decided. Social distancing measures could range from merely increasing space among people to complete social shut down. The former would have more deaths and a heavier and immediate burden on the health system, while the latter would initially ease the health system, but drive the economy into a deep recession later. So, it all boils down to who and when will assume the political responsibility, either of too many deaths and collapse of the health system or an economic recession.

An effective primary care system can mitigate the consequences of any pandemic

An intelligent version of social distancing would effectively balance things out so that vulnerable citizens be protected through isolation at varying degrees, while a lighter version of distancing would apply for everybody else. The prerequisite is a strong and effective primary care system, where the network of family physicians are fully aware of the health concerns and the condition of their clients and would prescribe the appropriate measures in each case. The scope of such a strong system should be to isolate and treat the ones who need protection and treatment at home rather, than moving the burden to the hospitals. The Italian experience is very eloquent: It is the hospitals that became hubs of the coronavirus and spread it to other patients, healthy visitors and personnel. Greece successfully solved this problem by taking the novel measure of moving the admission departments of hospitals outside the hospital, a rather clumsy and expensive measure to implement in an emergency. Home treatment by no means equals sub-optimal treatment nor means it obligatory home treatment. It only means that one shall not be hospitalized unless hospitalization is indeed the best option. By selectively protecting the ones who need protection the probability that they contract the disease becomes almost null. The probability of passing the disease on to others is also minimized since the infected will be in contact only with their physician and their trained and well-protected caregivers while, at the same time, observing all prescribed cleaning and disinfecting routines. Another aspect of a strong primary care system in the present epidemic would be the availability of enough molecular tests to map the prevalence of the virus in the population. S. Korea did it successfully. Should we have the resources to do that, it is pretty sure that our social distancing would be a lot milder, thereby mitigating the adverse economic and social consequences. The latter should also be part of the concerns of a sound system of public health at the same level as the concern of saving lives. Last but not least, an effective and robust primary care system would of course take a set of prophylactic measures, general and specific, to strengthen the health of the citizens beforehand (see down below).

Primary Health Care according to WHO: I. Multi-sectorial policy & action, II. Empowerment, III. Integrated health services
Primary Health Care according to WHO: I. Multi-sectorial policy & action, II. Empowerment, III. Integrated health services

The issue of cost-effectiveness

Would such a primary care system be cost-effective? The present opinion paper cannot answer this question with any certainty. An international study comparing the strength of primary care in 13 high-income countries found that strong primary care led to improved population health and lower health expenditure. A later study that compared the strength of primary care in 31 European countries used an alternative definition; it found that stronger primary care is linked to better population health, but also higher overall health expenditure (World Health Organization 2018). None of the studies had taken into account the case of a pandemic or even a major health emergency. The opinion of the present author is that the health systems of the great majority of European countries are far from the description given in the previous paragraph, and that the proposed above would be cost-effective, especially considering the following:

According to European Commission projections released on May 6, 2020, “Europe’s economy will shrink by 7.4 percent this year”. People are warned to expect the “deepest economic recession in European history”. Even if the virus dissipates, the economic fallout could pressure the world economy for months, if not years. In the US some forecasts predict a loss of more than 20 million jobs in April 2020 — a number that would wipe out a decade’s worth of job gains. U.S. gross domestic product fell at a 4.8 percent annual rate in the first three months of the year, and some economists believe it will contract at an annual rate of 30 percent or more in the current quarter (quoted from Stevis-Gridneff & Ewing, 2020). Greece is threatened by a recession of 10%!

Building an effective primary care system requires, of course, long-term planning and rather modest investment spread over many years. Such investment is expected to be accompanied by huge savings on the part of secondary and tertiary health units and will save a lot of troubles in contingencies like the present one. All it is required is steadily plucky political decisions on the issue of distribution of ever limited resources, according to national production-possibility frontier curves (Bloomenthal, 2020).

General prophylaxis

Generalities

Infections in general have only two possible outcomes: Either cure, or death. Once an infection-naïve healthy person has been infected, two factors will decide the outcome: A strong immune system and/or proper medication (allopathic, homeopathic, herbal, ayurvedic, traditional, or whatever would do the trick). The more important of the two is of course the immune system, but the availability of specific medications adds a safety margin. In a novel virus epidemic, “strong” refers solely to innate immunity. For a strong immune system, a healthy diet, a healthy microbiome, adequate sleep, adequate exercise and hydration are essential, as nearly every layperson knows. We will add a few more prophylactic factors below. General prophylaxis should be incorporated in the public health system but it is not, as modern medicine emphasizes treating the patients and not making them healthy or maintaining health.

A diagrammatic overview of the immune system
A diagrammatic overview of the immune system
A diagrammatic overview of the immune system

Immunostimulants are not generally recommended as prophylactics, at least without the supervision of a physician competent in integrative medicine; they should be reserved for cases with a weak immune system, applied for a short period. White blood cell (WBC) stimulating factors are a very good choice for patients with low WBC counts, for example due to chemotherapy. Some other medicines, mostly of herbal origin have gained popularity and they could also be used more freely, but not relied upon (see below, “Suggested therapeutic measures…”).

BCG vaccination in general prophylaxis

Special mention should be made to the so-called “trained immunity”. The term refers to reprogramming the innate immunity with the use of the time-honored BCG, a live, attenuated vaccine against tuberculosis, introduced in the early 20th century. BCG has been proven beneficial as a preventative of respiratory infections against a variety of viral insults, for individuals of any age. BCG vaccination affords partial protection and it remains to be proven if this is the case with SARS-CoV-2 too. The idea stems from the preliminary observation that BCG-vaccinated populations suffered less during the pandemic, in terms of morbidity, severity, and mortality. This association needs to be scrutinized in order that causation be proven (O’Neill & Netea, 2020).

BCG anti-viral innate immunity training
BCG anti-viral innate immunity training
BCG anti-viral innate immunity training. Credit: O’Neill & Netea, 2020

BCG vaccination of healthy human volunteers results in enhanced production of pro-inflammatory cytokines, such as IL-1β, TNF-α, and IL-6, when monocytes from these individuals are stimulated ex vivo with unrelated pathogens; these are precisely the cytokines that herald the cytokine storm in the severe cases (Giamarellos-Bourboulis et al, 2020); the difference is that this is done upon stimulation by the virus, thus creating a strong immune reaction that reduces viremia effectively, thereby reducing the chance of a protracted, low grade, and eventually uncontrolled, cytokine production with massive extracellular spill-over, especially in the presence of primed inflammasomes, in cases with some sort of co-morbidity.

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Possible epigenetic impact of BCG vaccination. Credit: O’Neill & Netea, 2020

Interestingly, these effects are accompanied by transcriptional, epigenetic, and metabolic reprogramming of the myeloid cells in the BCG-vaccinated individuals. The epigenetic changes are manifested as chemical modifications (methylation and acetylation) of the histone, resulting in enhanced chromatin accessibility, easier transcription of genes important for an improved innate response (Netea et al, 2016). Adequate epigenetic changes are of course dependent on methylation co-factors, like the vitamin B complex.

Healthy diet

There are several, sometimes conflicting, views on what constitutes a healthy diet; for all practical purposes, it includes balanced macronutrients and micronutrients, including trace elements, vitamins, prebiotic (soluble) fiber, etc. A detailed discussion is beyond the scope of the present opinion paper; nevertheless, flavonoids and terpenes merit special mention: Flavonoids provide much of the color of our salads, while terpenes provide the characteristic fragrance of herbs, fruit and spices. Flavonoids can mitigate the initiation of a cytokine storm by reducing NLRP3 inflammasome signaling (Lim et al, 2018). Several terpenes have anti-inflammatory properties (Da, 2015), the most notorious being β-caryophyllene from black pepper, basil and oregano (Francomano et al., 2019), limonene from citrus fruit (Yu et al, 2017), humulene from hops, coriander, black pepper, sage, and clove (Rogerio et al, 2009), myrcene from mango, thyme from bay leaves (Da, 2015) and others.

Perspective of the importance of Vit D and co-factors to health
Perspective of the importance of Vit D and co-factors to health
Perspective of the importance of Vit D and co-factors to health

Healthy microbiome

In general, the anti-infectious barrier of mucosae is efficient when the microbiome is complex and stable, in a eubiotic status with the host (Lazar et al., 2018). The intestinal microbiome is a signaling hub that integrates environmental inputs, such as diet, with genetic and immune signals to affect the host’s innate immunity and response to infection. Aberrations in the communication between the innate immune system and the gut microbiota might contribute to complex diseases (Thaiss et al, 2016). Aberrant microbial development during maturation of the innate immune system leads to defective immunological tolerance, which subsequently promotes exacerbated autoimmune and inflammatory diseases (Sekirov et al, 2010).

Microbiome and immunity
Microbiome and immunity
Propionate can bind to GPR-43 expressed on lymphocytes in order to maintain appropriate immune defence. Butyrate activates peroxisome proliferator-activated receptor-γ (PPAR-γ) leading to beta-oxidation and oxygen consumption, a phenomenon contributing to maintain anaerobic condition in the gut lumen. Decreased butyrate and propionate production leeds to secretion of less gut peptides by L-cells . The decrease in propionate contributes to the lower abundance of specific T cells (mucosal-associated invariant T cells (MAIT) and Treg) in the lamina propria of the gut. Altogether, such changes in the microbial environment and metabolites induce a leakage of pathogen associated molecular patterns (PAMPs) such as the lipopolysaccharide (LPS) that are increased in the blood, and trigger low-grade inflammation (see inflammasome activation above). Credit: Cani 2018, DOI: 10.1136/gutjnl-2018–316723

Periodic intake of probiotics is essential to maintaining a healthy immune system because the normal microbiome is under constant pressure due to nutrient-deficient western diet, frequent use of antibiotics and pollutants like glyphosate (Rueda-Ruzafa et al, 2019, Dechartres et al, 2019). Probiotics should always be taken with adequate prebiotics, either from food or from supplements, to help steady gut colonization.

Adequate sleep

Seven to 9 hours of sleep is essential to maintaining a competent immune system. Sleep deprivation caused elevations of TNFα, IL‐6, and CRP in the human plasma, of TNFα and IL‐6 in monocytes as well as enhanced mRNA expression of TNFα and its soluble receptor sTNFR1 in whole blood preparations (Hardeland 2018); it may also lead to severe disturbance of the functional rhythm of some T cells sub-populations (natural Treg and CD4+CD25-) (Bollinger et al., 2009). It also may lead to decreased phagocytosis and NADPH oxidase activity in neutrophils and a decrease in the levels of CD4+ T-cells which is related to changes in the Th1-related chemokine balance (Said et al., 2019). Blue light from TV and all sorts of electronic screens should be avoided at night (Shechter et al, 2018) and melatonin could be used, especially by the elderly, to help initiation and maintenance of quality natural sleep (Fourtillan, 2002). Sleep disturbances are closely related to melatonin dysregulation and its pronounced anti-inflammatory effects, especially in the elderly (see “Melatonin” below).

Healthy Endo-Cannabinoid System (ECS)

The ECS is a disperse system throughout the body; it is in constant interplay with all other organ systems promoting homeostasis in almost every aspect. Despite that, the ECS is still neglected and not included in the curricula of medical schools. For this reason a few introductory notes are in order (Battista et al, 2012). The ECS is the regulator of cognition, mood, nociception, energy metabolism, oxidative stress, and inflammatory processes (Tantimonaco et al., 2014).

The ECS consists of receptors, ligands to these receptors and enzymes that synthesize and degrade these ligands. The number of known endocannabinoid receptors is still growing to more than 55; the two most outstanding receptors are CB1R, mainly distributed throughout the nervous system and responsible for the psychoactivity of cannabis, and CB2R, mainly distributed on immune cells. Other receptors include TRPVx, GPR55, PPaRs, etc; all these receptors form dimers between them as well as heterodimers with other types of receptors, like opioid, dopamine, serotonin, adenosine, catecholamine and many others, thereby promoting a universal regulatory interplay throughout the body. The ligands to these receptors are the endocannabinoids (ECs), lipids of the eicosanoid family, derivatives of arachidonic acid (AA); the latter abounds in cell membranes; five of these are well characterized to date, but two are well studied: Anandamide (AEA) and 2-Arachidonoyl-Glycerole (2AG). ECs act in negative feedback loops, more or less like neurotransmitters, but, unlike them, they are synthesized and degraded on-demand, and not kept in micro-vesicles. Several formerly unrelated morbid conditions are now recognized as ECS deficiencies, including, among many, migraine, autism, fibromyalgia, irritable bowel syndrome, etc (Russo, 2016).

The endo-cannabinoid system: An outline of effects
The endo-cannabinoid system: An outline of effects
The endo-cannabinoid system: An outline of effects

The endocannabinoid system is involved in immunoregulation through the CB2 receptor and receptor-independent biochemical pathways as well. The mechanisms of immunoregulation by ECs include modulation of the response of different immune-cell classes, the effect on cytokine network and the induction of immuno-apoptosis; in brief, ECs down-regulate the innate and adaptive immune response in most, but not all, instances. Manipulation of endocannabinoids in vivo may constitute a novel treatment modality against inflammatory disorders.

It becomes obvious that the health of the ECS is of great importance in many ways, including the facing of a viral infection like COVID19. A healthy ECS depends on many factors, most importantly from proper nutrition and physical activity (McPartland et al, 2014).

· Dietary ω3 fatty acids seem to act as homeostatic regulators of the ECS, acting in opposite directions if consumed by obese or non-obese individuals. Little change in EC levels is seen in individuals with normal weight, not fed a high ω6 diet. Dietary ω6 are also essential, but should be in a balance to ω3s; suggested balance is ω3:ω6=1:1 to 1:3 for proper ECS signaling and prevention of peroxidation in general. Arachidonic acid is an essential component of the ω6 fatty acids.

· Probiotics and prebiotics have been mentioned already, but play a significant part in ECS health: They up-regulate CB2Rs (the ones on immune cells); they also modulate CB1Rs, depending on conditions, for instance, they down-regulate CB1Rs in obese individuals and help them gain less or no fat.

· Some flavonoids, like kaempferol, genistein, epigallocatechin gallate, and curcumin enhance the ECS; the same happens with some anthocyanidins, like cyanidin and delphinidin, although with a different mechanism.

· Phthalates, pesticides, additives to pesticides like piperonyl butoxide act as ECS disruptors, meaning that consuming organic food may be a sound protective measure, along with intake of detoxifiers, in case of health problems consistent with ECS deficiency not otherwise explained.

· Chronic stress impairs the ECS by decreasing levels of AEA and 2AG, and possibly through changes in CB1R expression too. Stress management may reverse the effects of chronic stress on ECS signaling. Anecdotal reports and common experience suggest that techniques such as meditation, yoga, deep breathing exercises and practicing of sex as well, exhibit mild cannabimimetic effects, thereby balancing the system.

· Exercise is also an ECS regulator: Long-term exercise leads to sustained elevation of ECs and predictable CB1R down-regulation.

· Chronic alcohol consumption and binge drinking likely desensitize or down-regulate CB1R and impair EC signaling. Alcohol is not compatible with a healthy ECS.

· Nicotine is an ECS deregulator: It induces EC production in some areas of the brain while decreasing them in others. It should be avoided too.

· Caffeine, acutely administered, potentiates CB1R-mediated effects through antagonizing adenosine at the A1 receptor (AA1R). At the undisturbed state AA1Rs tonically inhibit CB1R activity; Caffeine antagonism on AA1Rs sets CB1Rs free of inhibition, thereby enhancing ECS function, for example by letting 2AG activate CB1Rs. During chronic administration of caffeine, the effects are blurred by individual differences in adaptation. In general, CB1Rs are down-regulated.

· Chocolate: Cocoa contains small amounts of at least three N-acyl-ethanolamines with cannabimimetic activity, expressed either directly by activating cannabinoid receptors, or indirectly, by increasing AEA levels (di Tomaso et al, 1996).

Physical activity (PA)

PA is recognized as an independent “disease modifier”; a holistic, cost-effective method for prevention and positive modification of disease. The traditional view that PA engages the monoaminergic and endorphinergic systems has been supplemented by the discovery of the ECS. Direct and indirect evidence suggests that the ECS and PA influence one another in a regulatory and enhancing way (Tantimonaco et al., 2014).

Exercise workload and infection risk
Exercise workload and infection risk
Moderate exercise is associated with the lowest risk of infection. Credit: Nieman 1994, DOI: 10.1249/00005768–199402000–00002

Specific prophylaxis

Generalities

An efficient and adequate immune response entails, among other things, that at least some micronutrients be available at appropriate amounts in the system; this has been demonstrated in both animal and human studies. Deficiencies of micronutrients affect both innate and adaptive immune responses and can impair immune functions, leading to deregulation of the normally coordinated host response to infection, thereby enhancing the virulence of pathogens (Wintergerst et al, 2007). In the present COVID19 pandemic it is precisely this coordination of the immune response that is lost in some cases, leading them to death; these are the ones that evolve into a combination of ARDS and generalized immune dysregulation. We will now look into the role of some micronutrients (vitamins and trace elements) on immunity and the possible role of supplementation for the prevention and/or for establishing a healthier immune system as the basis of treatment of viral diseases.

Micronutrients (credit: https://www.nutritional-insight.co.uk/)
Micronutrients (credit: https://www.nutritional-insight.co.uk/)
Micronutrients (credit: https://www.nutritional-insight.co.uk/)

These days the web is full of warnings that “No supplement will cure or prevent coronavirus disease” or “No foods or supplements can prevent coronavirus”. It is a totally different thing to say that “nutrients (or supplements) won’t prevent COVID19” and to say “nutrients (or supplements) are worthless fighting COVID19”; because they won’t prevent it for sure, but they will certainly prepare the immune system to fight the virus with a well-balanced response. It is also beyond reasonable expectation that nutrition or supplementation shall cure the disease, especially if those nutrients be administered post hoc; there will be no time for them to reach proper tissue concentrations, regulating biological pathways and influence the outcome. We should acknowledge that modern western societies, although overfed, are severely malnourished, and this is a public health issue of utmost importance, carrying political liability too.

Pyridoxine (vitamin B6)

Its deficiency in humans is accompanied by imbalanced Th1/Th2 response: Suppression of Th1 and promotion of Th2, thereby decreasing adequate initial fighting of the virus (mainly decrease in pro-inflammatory cytokines IL-1β) and indirectly hindering antibody production. Adequate supplementation reverses Th1 response (Rall & Meydani, 1993).

Cyanocobalamine (Vitamin B12)

It acts in concert with vitamin B6 and folate, promoting nucleic acid and protein biosynthesis; said effect is especially pronounced in highly prolific tissue, like immune cells. B12 deficient patients showed an abnormally high CD4+/CD8+ ratio and suppressed NK cell activity, restored by methyl-cobalamine (Tamura et al., 1999, Wintergerst et al, 2007).

Folate

Its general role in biosynthesis has been mentioned in B12 above. Folate deficiency impairs Th1 response. Supplementation improves overall immune function especially in the elderly by altering the age-associated decrease in NK cell activity (impaired killing of virus-infected cells) and by supporting Th1 response. Over-supplementation suppresses NK cells (Wintergerst et al, 2007).

Ascorbate (Vitamin C)

For most mammals vitamin C is a hormone; since there is no storage system for this vitamin in humans, they have to replenish it every day from fruit and vegetables to fight oxidative stress. The elderly, chronic smokers, athletes, those exposed to environmental pollutants [that means practically everyone (Gehin et al, 2006)] are at high risk for chronic vitamin C deficiency (Wintergerst et al, 2006, Wintergerst et al, 2007).

Image for post
Image for post
Vitamin C and the immune system. Jafari et al, 2019, DOI: 10.1007/978–3–030–16073–9_5

Vitamin C enhances innate immunity since monocyte-macrophage differentiation is helped by ascorbate and associated with increased expression and function of the transporter protein SVCT2 (Qiao & May, 2009), essential for intracellular accumulation of active vitamin C (Savini et al, 2008). This transmembrane transporter of vitamin C is dependent on the concentration of sodium, magnesium, and calcium in the extracellular fluid (Gess et al, 2009). Of these three cations, magnesium is usually deficient, especially in the elderly, and needs supplementation. Adding magnesium ions to the vitamin C solution enhanced the anticancer effects of vitamin C by increasing the vitamin C transport activity of SVCT-2 (Cho et al., 2020); we could not find analogous evidence in the literature for viral disease. Vitamin C insufficiency induces hyper-reactive immune responses against viral and bacterial infection or chemicals, from the lungs. It plays a critical role in in vivo anti-viral immune responses against influenza virus through the increase of IFN-IL-1α/β production, in case of insufficiency. Therefore, it might be possible that maintaining sufficient levels of vitamin C in the plasma by continuous supplementation could effectively prevent in vivo pathogenesis of influenza virus at the initial stage of viral infections and possibly progression to pneumonia as well (Kim et al., 2013, Hemilä, 2017). Vitamin C has the ability to regenerate the antioxidant potential of other antioxidants, like vitamin E, acetaminophen and glutathione. This is of special importance in treating some ARDS cases of COVID19 with acetaminophen, which might quickly be exhausted and become toxic to the liver (Blough & Wu, 2011).

Retinoids (Vitamin A)

Supports Th2 anti-inflammatory response. Retinoid deficiency impairs innate immunity by hindering the maintenance and repair of epithelial barriers. Deficiency is also associated with diminished phagocytic and oxidative burst of macrophages, reduced NK cell activity, increased production of IL-12 and TNFα, and a decrease in antigen-specific response. Supplementation down-regulates IFN-γ, TNF-α, enhances IL-4, IL-5, IL-10 secretion, and improves antibody titer response to vaccines. Over-supplementation, among other things, suppresses T-cell activity as well as cytokine and anti-body production (Wintergerst et al, 2007).

Secosterols (Vitamin D complex)

The beneficial role of vitamin D in viral infections is well‐described by several epidemiological studies, supporting the notion that higher levels of vitamin D are associated with better prognosis and improved outcomes. It seems that the same applies in the case of COVID19, based on mortality data vis a vis levels of vitamin D by country and subgroup (Ilie et al, 2020). The role of this hormone/vitamin is both complex and intriguing in viral disease. Its importance in the maintenance of sound health of the public is for some reason almost a well-kept secret. The interplay between viral infections and vitamin D includes induction of an anti‐viral state of the host, induction of functional immunoregulatory features, interaction with cellular and viral factors, induction of autophagy and apoptosis of diseased cells, and genetic and epigenetic alterations.

Vitamin D: A crucial immune regulator
Vitamin D: A crucial immune regulator
Vitamin D is a crucial immune regulator. Vitamin D status of the host as defined by serum, extracellular 25(OH)D levels impact immune response, as 25(OH)D is the substrate for CYP27B1 (left part). Vitamin D action in immune cells is reliant upon the local production of active 1,25(OH)2D within the macrophage (right part). A complex interplay between monokine signaling, that can both be responsive to and stimulatory of 1,25(OH) 2 D synthesis, and regulatory signaling among innate and adaptive immune cells is shown. (Credit: Chun et al, 2019, DOI: 10.3389/fendo.2019.00718)

Crosstalk between vitamin D and intracellular signaling pathways provides an essential modulatory effect on viral gene transcription. Megadoses of vitamin D seem to be in vogue lately, probably in an attempt to swiftly correct long-standing insufficiency; nevertheless, evidence exists that such unphysiologically high doses for the treatment of viral infections are not effective, in contrast to low or medium everyday doses over long periods (Bergman et al, 2013), administered as a prevention rather than a cure. Its epigenetic role includes modification of histone methylation and viral enhancement of methylation of the promoter gene of VDR (vitamin D receptor) (Teymoori-Rad et al, 2019). Vitamin D is indeed a double-edged sword: On the one hand it induces IL-1β expression, but, on the other hand, it inhibits NLRP3 activation, thereby avoiding NFкB enhancement of inflammation. It is excellent as a preventive measure; optimally, the patient should be prepared well in advance by maintaining levels of 25-OH-D3 far higher than those believed upper normal (Wintergerst et al, 2007). The present author advises 25-OH-D3 levels of between 60–100 ng/mL as adequate for the regulation of inflammasome and oncogenes. Absorption and response to vitamin D supplementation vary according to the availability of Magnesium (see “Magnesium” and “Boron” below).

Tocopherols & Tocotrienols (Vitamin E complex)

It optimizes and enhances Th1 response and reduces PGE2 production by macrophages, which inhibits Th1 cytokines. It has improved the innate immune function of elderly people, by enhancing NK-cells in particular. Its clinical role is not as clear as with other micronutrients (Wintergerst et al, 2007).

Magnesium (Mg)

Conversion of stored, inactive vitamin D (25-OH-D3) into its active form (1,25-OH2-D3) is needed before exerting its biological functions. This conversion is mainly dependent on the bioavailability of magnesium, meaning that in case of latent magnesium deficiency, a very common condition in the elderly, vitamin D supplementation alone will not help. Conversely, magnesium supplementation was shown to markedly reduce the resistance to vitamin D treatment (Uwitonze & Razzaque, 2018). Mg (and other minerals) is essential for other biological processes, ie ascorbate transmembrane transport (see “Vitamin C”).

Magnesium: An important co-factor of Vitamin D
Magnesium: An important co-factor of Vitamin D
Magnesium is an important co-factor of Vitamin D. It interferes with its metabolism in at least 8 occasions. Credit: http://is.gd/MgVitaminD

Mg is the most abundant divalent cation in living cells. It plays a direct role in the immune response: it acts as a co-factor for immunoglobulin and C-3 convertase synthesis, immune cell adherence, antibody-dependent cytolysis, IgM lymphocyte binding, macrophage response to lymphokines and T helper–B cell adherence (Galland, 1988). Mg is considered as a second messenger ion, mediating immunity processes through its transmembrane transporters (Schmitz & Perraud, 2016).

Boron (B)

Dietary boron upregulates 25-OH-D3 by increasing its bioavailability. It acts as an inhibitor of microsomal 24-hydroxylase, chiefly responsible for the catabolism of vitamin D (Miljkovic et al, 2004). It could be considered as an emergency supplement, in cases of low levels of 25-OH-D3. Additionally, boron may up-regulate 17β-estradiol levels in women, thereby improving their immune response to threats, like viruses, through estrogen receptor-dependent and -independent mechanisms (Khan & Ahmed, 2016) (see “Estrogens” below).

Zinc (Zn)

Zn influences both innate and acquired immune functions, supports Th1 response without affecting Th2 response, and is an essential cofactor for thymulin, a modulator of cytokine release. This trace metal appears to inhibit the virus-cell interaction and merging with coronaviruses, thereby preventing or slowing coronavirus entry into host cells (Phillips et al, 2017) and appears to reduce SARS-CoV virulence by inhibiting its papain-like protease, essential for the cleavage of proteinic sites on the host cell surface (Han et al., 2005). Although there is no storage system for zinc in humans, and zinc needs to be taken in regularly, there exist special risk groups susceptible to subclinical Zn deficiency: Vegetarians (decreased absorption), elderly (insufficient intake and absorption), patients with intestinal diseases (decreased absorption), children (insufficient intake and absorption), pregnant and nursing women (increased needs), and patients with chronic infections or inflammatory diseases (increased requirements) (Wintergerst et al, 2006, Wintergerst et al, 2007). Zn supplementation requires caution, as it may lead to copper (Cu) malabsorption that may result in the clinical triad: anemia, leucopenia, and myeloneuropathy (Wazir & Ghobrial, 2017).

Selenium (Se)

Se influences both the innate and acquired immunity by playing a key role in redox regulation through the mediation o glutathione peroxidase and other selenoproteins. It contributes to the optimization of the immune response by balancing Th1/Th2 activity. Se deficiency is common in the elderly; adequate Se prevents viruses to undergo mutations to more virulent forms in the host (Broome et al., 2004). In healthy subjects supplementation augmented T-lymphocyte-mediated immune response, enhanced proliferation, increased the response to antigen stimulation, increased cytotoxic and NK cell activity, and increased IFN- (Th1 response). Supplementation of the elderly restores the age-related defect in cell proliferation (NK cell and cytotoxic activity) and prevents increased susceptibility to inflammatory disease. As with other micronutrients, it seems that the current RDA is suboptimal (Wintergerst et al, 2007).

Iron (Fe)

Iron is essential for the maintenance of multiple basic cellular functions and in that sense it also affects cellular immunity, both in the deficient and in the over-abundant state, more so in the latter. T-cells express surface transferrin receptors, more pronounced on the Th1 side. Antigen production is not affected (Wintergerst et al, 2007). In the COVID19 pandemic (and other flu-like conditions for that matter) the importance of Fe is even higher: In some cases, seemingly of young age and free of comorbidities, there is uncompensated production of ferric (Fe+++) and ferryl (Fe++++) ions as products of cell-free heme catabolism; both iron radicals are involved in lipid oxidation, particularly of alveolar cell membranes, thereby adding to the propensity towards the establishment of ARDS (Schaer & Buehler, 2013).

Melatonin

Melatonin is a highly conserved molecule during evolution; a hormone with multiple physiological effects, including the all-important cross-reactivity with the endocannabinoid system. In its anti-inflammatory capacity, melatonin decreases the TLR-mediated downstream gene expression in infected macrophages and the subsequent NF-kB-dependent gene expression, NLRP3 inflammasome activation and IL-1β and IL-6 production via SIRT1. Modulation of the inflammatory response, the reactive oxygen species production and the related oxidative stress represents a potential novel pharmacological approach to ameliorate the host reactions against viral infections and their long-term consequences. Melatonin reduces oxidative lung injury and inflammatory cell recruitment during viral infections. In fact, the age-related decline in melatonin production is one proposed mechanism to explain why children do not appear to have severe symptoms while the elderly do, as is the case in the COVID19 pandemic (Silvestri & Rossi, 2013, Peng et al, 2018). The anti-oxidant property of melatonin is responsible for the synergism with anti-viral drugs (Huang et al., 2019).

Melatonin anti-inflammatory effects
Melatonin anti-inflammatory effects
The multiple direct and indirect anti-inflammatory effects of melatonin. Hardeland 2018, DOI: 10.1111/jpi.12525

Melatonin markedly reduces the oxidative breakdown of lipids, especially in vivo, both directly and through its metabolites, thereby preserving membrane integrity and fluidity (Reiter et al, 2014). Lipid peroxidation of alveolar cell membranes, a degradative pathogenic process observed in some cases of SARS-CoV-2 induced ARDS, may be generated by ferric (Fe+++) and ferryl (Fe++++) radicals, produced from extracellular heme degradation during sepsis; in the same pathophysiological frame, it can counteract local NO consumption (Simko et al., 2018). Melatonin, apart from acting as an antioxidant, can exert its protective effect by preventing the release of iron radicals from cell-free heme (Shaeib et al., 2015); it could be considered as a preventative of the above morbid mechanism in cases of acute respiratory infections, at least for the elderly and the compromised. For patients already in the ICU, the addition of acetaminophen is a proven therapeutic measure (Janz et al., 2015); no interactions have been reported between the two substances (Drugs.com). Melatonin in combination with toremifene, a selective estrogen receptor modulator, is one of six drugs that have been selected for repurposing studies for the treatment of COVID19 patients through the novel method of computational network-based drug discovery (Zhou et al., 2020).

Administration of melatonin to humans at pharmacological concentrations is essentially non-toxic; it is considered a safe supplement with few contraindications and precautions for its use: Pregnancy, certain autoimmune disorders and daytime administration. Its therapeutic window is also very wide, ranging from 0.1 to 100 mg/d, depending on the individual and the condition treated (Peres et al, 2006, Silvestri & Rossi, 2013).

Attention to the above measures should suffice to keep one healthy, or to be more precise, to lessen the incidence, the duration, the intensity of symptoms and complications of acute respiratory infections (ARIs), including the common cold, the seasonal flu (influenza) and other common cold-like and flu-like conditions due to rhinoviruses, adenoviruses coxsackie-viruses, parainfluenza viruses, respiratory syncytial virus, group A and C beta-hemolytic streptococci, chlamydia, etc.

Overview of therapeutic measures for acute respiratory infections (ARI), applicable in the era of COVID19

The prevailing treatment

Apart from adequate supportive treatment in the ICU (careful mechanical ventilation, prone positioning, extracorporeal oxygenation, inhaled vasodilators, blood transfusions and other measures as indicated individually) (Kazory et al, 2020), the critical factor for a favorable outcome of ARDS is the quick and effective treatment of the underlying cause (Umbrello et al, 2017). In the case of SARS-CoV-2 no specific anti-viral medicine is available, but remdesivir, an adenosine analog that has been used against Ebola, SARS and MARS, has shown some success in COVID19 patients (Martinez, 2020) and is now given “emergency use authorization” by the FDA based on an animal study (Williamson et al., 2020), while it is still characterized as “experimental”. The combination of melatonin and anti-viral drugs is also worth studying (Huang et al., 2019). Giamarellos-Bourboulis et al (2020) proposed the use of tocilizumab for the mitigation of IL-6 over-expression. Other antiviral agents do not seem to merit even mentioning. From the integrative standpoint, what remains to be done is taking proactive measures addressing the inflammatory process that goes out of control (Piantadosi & Schwartz, 2004). But most COVID19 cases will not need anything as drastic.

Other treatment options

In most cases the course of COVID19 varies between totally asymptomatic to a mild flu-like syndrome. Most people will cope with it successfully, without even consulting their family doctor. These cases do not need any additional help, apart from the above general measures (see sections B and C above) that everyone should observe for maintaining an always ready and effective immune system. If our country of residence has also a robust and effective primary care system in place (see section A above), then the outlook should be optimistic in any epidemic, novel, or otherwise.

When contracting an ARI, some people try to stop the course of the disease with different measures (OTC medication, multi-vitamin formulations), often traditional (garlic, teas) and sometimes even irrational (drinking raki, tsikoudia, grappa or other strong alcoholic beverages), believing that they will “kill the virus”.

In the present contingency we would advise abstinence from all cold- and flu-remedies, either conventional or traditional, especially without medical supervision. Such measures might have been safe in past common colds and cases of flu, but the clinical course of COVID19 might take an altogether different course (see above). The only measures that one could safely take to favorably influence the course of mild flu-like syndromes are vitamin C in high doses, Magnesium, and Zinc. In case one be deficient in vitamin D, E, iron, Se, etc, there is no time to replenish and, on the other hand, aggressive supplementation might trigger an unfavorable immune response in delicate individuals; for instance, taking too much vitamin D might trigger IL-1β production, which could be the herald of a cytokine storm. We can never be sure what exactly will happen in each case, especially in the community.

Immunostimulatory herbal remedies

Some herbal remedies are very popular with a lot of people worldwide and deserve special mention and of course more careful research.

Elderberry extract shows definite antiviral properties against another novel human coronavirus (CoV-NL63), mainly due to its caffeic, chlorogenic and cumaric acid content (Weng et al., 2019);

Larch arabinogalactan has been tested in both cell and animal models and proven capable of enhancing natural killer cells and macrophages as well as the secretion of pro-inflammatory cytokines. In a clinical study larch arabinogalactan was shown to decrease the incidence and symptoms of common cold infections. A direct immunostimulatory effect via the gut-associated lymphoid tissue is proposed, but there is a possibility of indirect action through gut microbiota-dependent mechanisms (Dion et al, 2016);

· Medicinal mushrooms that contain protein-bound polysaccharide-K show antiviral effects mediated through induction of inflammasome and production of IL-1β, by a TLR2- and NLRP3-dependent mechanism (Yang et al., 2014);

· Echinacea angustifolia and purpurea are clinically more controversial, but studies on human macrophages prove their immunostimulatory effect. Interestingly, alkylamines of E. purpurea act as CB2R-agonists, thereby moderating its immunostimulatory effect in a way similar to some cannabinoids and the terpene β-caryophyllene (Burger et al, 1997, Karsch-Völk et al., 2015, Catanzaro et al, 2018).

Other commonly used natural immunostimulatory and antiviral agents, including the following, do not appear to increase IL-1β or IL-18 as a part of their immunomodulatory actions. Several of these, in fact, reduce these cytokines and may restore immune homeostasis. These are, therefore, likely safe to use both prior to, and during, COVID-19 infection. Whether these agents mitigate the symptoms or virulence of COVID-19 is unknown and therefore the expected benefit of these agents during true COVID-19 infection is unknown.

Allium sativum (garlic) inhibits the production of IL-1β and IL-6 (Moutia et al, 2018) and does not make much sense in the initial phase. It could of course be part of a healthy diet. It contains several families of active compounds with a sulfur base that can be extracted into complex preparations with anti-oxidant and immunomodulatory effects.

Quercetin, an herbal polyphenol, has anti-inflammatory and antiviral activities; it also attenuates lipid peroxidation, platelet aggregation and capillary permeability (Li et al., 2016). The complexity of biological actions and the low level of evidence cannot support its use with any degree of reliability.

· Astragalus membranaceus may enhance IL-6 production and multiply interfere with immune balance (Auyeung et al, 2016).

· Agaricus blazeii is rich in β-glucans (immunomodulating polysaccharides). Its anti-inflammatory effects have been studied in pre-clinical infection models not related to viral infections. These effects are mediated through stimulation of innate immune cells, such as monocytes, NK cells, and dendritic cells, and the amelioration of a skewed Th1/Th2 balance and inflammation, through the reduction of TNF, IL-1β and IL-6 production levels (Hetland et al, 2011).

· Andrographis paniculata: This plant should attract more research interest in the context of COVID19 because preclinical evidence suggests important antiviral actions (H1N1). Its main active substance is andrographolide, a suppressant of lung inflammation induced by non-typeable Haemophilus influenzae in a mouse model, through regulation of Nrf2 expression, producing an anti-oxidant effect. Andrographolide also reduces pulmonary immune cell infiltration and expression of cytokines and chemokines, including TNF-α, IL-1β, and CXCL1. Interestingly, andrographolide is an antimalarial and reminds us of chloroquine, but it is a protease inhibitor (Dai et al., 2019), while chloroquine exerts alkalinizing action at the plasmodial vacuole.

Special caution is needed with patients suspected to have COVID19 or influenza, precisely because the course will depend upon a delicate balance between immunostimulation, desirable in the initial phase, and immunomodulation in case they later tend to develop a persisting cytokine storm in the lungs combined with generalized immune dysregulation (Hellenic Institute for the Study of Sepsis, 2020). All the above herbs should be avoided, especially as self-remediation, precisely because one can never know the titration, the exact phase of the course of the disease, how potent the effect of herbs will be and, most importantly, to what direction.

Treatment considerations for the severely ill

The toughest clinical issues will obviously be faced with those few cases that will develop an uncontrolled immune reaction, which will necessitate hospitalization, ICU admission and/or intubation.

The critical point seems to be at about the 5th to 7th day; at that point, the disease will either subside or evolve into a respiratory and immune imbalance syndrome.

ARDS of any etiology is closely related, apart from other factors, to the increase in CFH (Cell-Free Hemoglobin) levels in the lung tissue. An increase in CFH is found in 80% of septic conditions and is associated with nosocomial mortality. This approach encourages research for innovative therapeutic proposals.

1. Glucocorticoids (GCs)

GCs have been for years the basic therapeutic measure one considers when faced with immune hyperactivity. This applies of course to COVID19. Down-regulation of systemic inflammation at some point, probably between days 5 and 7, is essential to improving survival. Prolonged low-to-moderate dose GC therapy promotes the down-regulation of inflammatory cytokine transcription at the cellular level unless acquired GC resistance is already established (Meduri et al, 2009). Although GC administration looks like the indicated measure, and in fact it is, not all inflammatory components are amenable to GC treatment; this leads to inconsistent results of GC treatment of ARDS. A whole array of pro-inflammatory miRNAs, associated with TLRs and NFκB signaling (Juknat et al, 2019), has been shown to play a critical role in the enhancement of cytokine storm in ARDS (Umbrello et al, 2017), and this resolves the “mystery” of incomplete response to GCs because miRNA-associated mechanisms do not respond to them; fortunately, this part can be covered by cannabinoids (see “Phytocannabinoids (CBD & THC)” below). The possible regulatory role of estrogens on miRNAs is still inconclusive but might surprise us in the future (Klinge, 2009).

2. Anti-sera

So far, the population (the so-called “herd”) does not have antibodies, nor the ability to produce antibodies quickly, as the epidemic is not allowed to proceed normally. Besides, little is known about the ability of SARS-CoV-2 to stimulate the production of antibodies by the host, and for how long these antibodies will afford protection. Controversy exists concerning the possibility of relapse or recurrent infection.

· Convalescent hyper-immune anti-sera: Their production has been discussed (de Alwis et al, 2020) but does not seem to be in any government’s plans.

· Monoclonal antibodies against the SARS-COV-2 S-protein complexes, which bind the virus to ACE2 receptors, are believed to prevent the virus from attaching to the receptors. The use of such antibodies is only experimental at present (Kumar et al, 2020). Another attempt has led to the preparation of a human monoclonal antibody, the so-called hmAB47D11, active against both SARS-CoV and SARS-CoV-2 S-protein complexes (Wang et al., 2020). It should be kept in mind that both hyper-immune globulin and vaccines carry the risk of antibody-mediated disease enhancement. They should be tested extensively before they are used on humans.

· Tocilizumab is a monoclonal antibody against IL-6, therefore it is indicated when an increase of IL-6 is observed, with the rationale of preventing the developing cytokine storm by removing produced IL-6. Repeated administration has shown encouraging results in preliminary studies (Luo et al., 2020), but caution should be exercised while using it because the fate of all these immune complexes is uncertain, and the exclusive specificity for IL-6 is not verified.

3. Possible measures to counter cell-free hemoglobin (CFH) effects

Extracellular hemoglobin (CFH), unlike that found in erythrocytes, is a highly toxic substance, especially if it rises beyond the capacity of the body’s compensatory systems. Toxicity is exerted by the following mechanisms (Janz & Ware, 2015, Batra et al, 2016, Schaer & Buehler, 2013):

• Local consumption of NO → Vasoconstriction → Ischemia

• Oxidation of Fe++ into ferric (Fe+++) and/or ferryl (Fe++++) radical → Oxidation of lipid membranes, with particular clinical emphasis on alveolar cell membranes

• Activation of NF-κB → Inflammation

• Endothelial damage → Vascular hyperplasia

Pathophysiology of cell-free hemoglobin
Pathophysiology of cell-free hemoglobin
Credit: Janz & Ware, 2015

Activation of these mechanisms promotes the progression of sepsis into multiple organs’ failure.

The compensatory mechanisms against CFH increase are related to the presence of enough haptoglobin, hemopexin and heme-oxygenase-1.

· Haptoglobin (Hp): It is classified as an acute-phase protein of inflammation. It binds stoichiometrically to CFH and makes it susceptible to phagocytosis by macrophages carrying the CD163 receptor; there it is converted to bilirubin and excreted in the bile. Hapotglobulin administration is presently a treatment option in Japan.

· Hemopexin (Hpx): It is also classified as an acute-phase protein of inflammation. It binds heme and makes it susceptible to phagocytosis by macrophages that carry the APOER receptor. It is an IL-10 up-regulator (Hassaan et al, 2015), therefore it has one more role as a potent anti-inflammatory factor. Hemopexin, either recombinant or from human plasma, is available for experimental use. It should be considered for the treatment of specific COVID19 cases.

· Heme-oxygenase-1: Converts heme to bilirubin. It is up-regulated when the Hp-Hb complex enters the macrophage. It increases substantially in cases of sepsis and ARDS. It is expressed by all lung cells. It controls inflammation and endothelial damage to the lungs. It is available for experimental use and it could be considered for the treatment of specific COVID19 cases.

· Administration of NO: It is a feasible therapeutic measure in the modern ICU environment. It reverses vasodilation and ischemia. It can be given as inhaled gas through a mask or the endotracheal tube under close monitoring of pulmonary artery pressure, ejection fraction, Met-Hb and NO2 (Bloch et al, 2007).

· Acetaminophen, melatonin and other antioxidants: They have been mentioned above. They are time-honored, inexpensive and easily administered through the digestive tract. Acetaminophen and melatonin act favorably on the ferryl radicals, preventing the formation of ferric myoglobin and F2-isoprostanoids, and renal damage (Janz et al., 2015, Janz & Ware, 2015). Antioxidants are not an independent treatment option, because exogenous administration does not prevent the oxidation of the cells of the alveoli by the ferric and ferryl radical. However, they are a necessary supplement to the administration of acetaminophen, because they replenish its antioxidant potential. The above mechanisms are particularly important in septic conditions because the latter independently favor the release of CFH from red blood cells that are hemolyzed; transfusions are regularly used in the ICU for a good reason, but they worsen the problem of CFH. The therapeutic application of dialysis, also commonly used in cases of multiple organ failure, further exacerbates CFH due to mechanical hemolysis.

4. Chloroquine, OH-Chloroquin + Azithromycin

Chloroquine is a broad-spectrum inhibitor of endocytosis of artificial nanoparticles and is well studied in this area. The SARS-CoV-2 virus is 60–140 nm in size, so it falls to the size scale of nanoparticles and is spherical in shape, like well-studied synthetic nanoparticles. Therefore, it is understood that chloroquine can block the entry of the virus into cells by the same mechanism that prevents other nanoparticles (Hu et al, 2020). It should be used under the MEURI framework due to its several potential adverse effects (Cortegiani et al, 2020).

Image for post
Image for post
Credit: Mokobi 2020 (modified), https://microbenotes.com/chloroquine/#chloroquine-and-covid-19

The endocytosis of nanoparticles is normally achieved with the help of clathrin, a three-legged protein attached to the intracellular part of the appropriate transmembrane receptor (in this case the receptor of the angiotensin-converting enzyme (ACE2R). Chloroquine reduces the production of PICALM, a cargo-selecting adaptor of clathrin that senses and drives membrane curvature, thereby regulating the rate of endocytosis, thus making it difficult for the virus to enter the cell.

The SARS-CoV virus, identified in 2003, and the human coronavirus NL63 (HCoV-NL63), identified in 2004, have been linked to ACE2R; they cause intracellular virus transmission in the same way. For SARS-CoV, clathrin-independent endocytosis mechanisms have also been described, involving cholesterol- and sphingolipid-rich lipid raft microdomains in the plasma membrane (Wang et al., 2008). Chloroquine has been shown to have anti-SARS-CoV activity in cell cultures even when administered after the virus enters the cell, suggesting that other mechanisms of its antiviral activity may be involved.

Once endocytosis of the virus has been completed, in order for its RNA to access the cytoplasm, the protein complex of the spikes on its surface must be cleaved into S1 and S2 component by furin (Tsiambas et al., 2020) or other proteases named cathepsins, activated after acidification of the endosome. The cleaved spike is thus enabled to perforate the membrane of the endosome and let the virus casing fuse with the membrane of the endosome; then viral RNA is released into the cytoplasm. It is already known from the study of the action of chloroquine in malaria that chloroquine alkalinizes the previously acidic content of the endosome, which makes it difficult for the virus to move from there into the cytoplasm. This last step is necessary to start the multiplication of the virus using the resources of the host.

The aforementioned inhibition of endocytosis is closely related to blockade of autophagy; several autophagy inhibitors have been tested as blockers of the cytopathic effects of SARS-CoV-2; some proved active but inferior to chloroquine (Gorshkov et al., 2020).

Azithromycin (AZM) is an antibiotic of the macrolide class with excellent penetration in tissues including macrophages and monocytes. As all macrolides it exhibits some off-label immunomodulatory effects that have not been studied extensively. Interestingly, AZM was less frequently associated with changes in measured immunological markers compared to the other macrolides; there is evidence that it inhibits IL-1α, IL-1β, and IL-6. This is the rationale of using it in conjunction with chloroquine (Zimmermann et al, 2018).

5. Colchicine

Colchicine (Colchicine, Drugbank.ca) is an old and inexpensive medicine; it is established as a key drug in the treatment of gout, familial Mediterranean fever, Behcet’s and other inflammatory conditions, particularly those prone to fibrosis) and with well-known side effects (mainly gastrointestinal; it also has deeper biological effects like anti-mitotic and de-polymerization of tubulin). It can, therefore, be easily used off-label, if necessary, omitting the time-consuming stage of phase I and II studies.

Colchicine expresses anti-inflammatory action in the following ways (Leung et al, 2015):

· Suppresses the primary immune response, inhibiting elements of the inflammasome (NALP3), resulting in non-activation of caspase-1.

· Prevents the release of chemotactic agents and, ultimately, the attraction of neutrophils to the site of inflammation.

· Prevents the attachment of neutrophils to the endothelium by inhibiting selectin-E (in low doses).

· Promotes the elimination of selectin-L from neutrophils and prevents their further mobilization (in high doses).

· Inhibits neutrophil activation and IL-1, IL-8 and H2O2 release.

· Inhibits VEGF and endothelial proliferation.

Additionally, colchicine has antitumor effects at high doses; at low concentrations it arrests polymerization of tubulin while, at high concentrations, it promotes microtubule de-polymerization. At high doses it may incite severe toxicity to normal tissues, which is of course a limiting factor both to the dosage and to the duration of treatment.

Based on the above, the anti-COVID19 use of colchicine appears to be based on its anti-inflammatory properties, particularly by suppressing the primary immune response, when the latter is not useful anymore and is, in fact, out of control and threatening to the patient.

6. Estrogens

For all the reasons stated in the paragraph on gender differences (see “Gender differences” above) the present author agrees with professor Suba (2020) that estrogens in the conjugated form of Premarin may prove one of many reasonable means to treat COVID19-induced ARDS in both men and women without adverse effects, because “it exhibits similar DNA repairing and genome stabilizer effects like endogenous estrogens.

Protective effects of estrogens in COVID19
Protective effects of estrogens in COVID19
Protective effects of estrogens in COVID19: A graphical representation. Credit: di Stadio A et al, 2020

Premarin treatment may prevent respiratory virus infections in susceptible people. Premarin may achieve dramatic improvement in patients suffering from acute respiratory distress syndrome; however, the result is not prompt as estrogen-induced gene expression and new protein synthesis takes at least 24 h”. Besides, according to Newton et al (2016), the activation of estrogen receptors residing on lymphocytes may decrease viral load due to increased production of types I and III of interferon. Estrogens could also act synergistically with cannabinoids for a better outcome, based on their additive and non-opposing effects on particular aspects of innate immunity. Administration of boron may up-regulate 17β-estradiol levels in women, thereby improving their immune response to threats, like viruses, through estrogen receptor-dependent and -independent mechanisms (Khan & Ahmed, 2016). This reminds us of the effect of boron on the bioavailability of vitamin D; it could, therefore, be used in men and women with low estradiol or even along with estrogens, to boost their effect.

7. Spironolactone and other ACE2-related drugs

On account of the central role that furin and ACE2R have in the process of cell invasion by the virus, pharmaceutical manipulation of either or both of these endopeptidases might be promising. Furin manipulation looks very tricky: There is no way to predict the total effect of furin inhibition, due to its ubiquity and its physiological importance. Preliminary research exists for influenza virus H7N1 (Becker et al, 2009). On the other hand, free-floating ACE2Rs could bind some of the viruses, thereby protecting membrane attached ACE2R molecules by reducing the viral load on the alveolar epithelia. Interestingly, spironolactone can increase ACE2R expression in plasma by 3–5 times (Cadegiani 2020); incidentally, spironolactone has also estrogen-mimicking properties that could add to its overall therapeutic effect. This is purely hypothetical reasoning, but one worthy researching, because spironolactone is an old and inexpensive drug with benign adverse effects.

Apart from spironolactone, a readily available inexpensive drug, another promising approach for the future could be the production of recombinant ACE2R, and even AT-1,7 and AT-1R blockers (Verdecchia et al, 2020).

8. Phytocannabinoids (CBD & THC)

According to all studies to date (Nichols & Kaplan, 2020), there is no doubt that CBD and THC have immunomodulatory and anti-inflammatory effects. By “immunomodulatory” we mean essentially immunosuppressive since they generally suppress the proliferation and activation of mitogen-stimulated T-cells, as well as the production of pro-inflammatory cytokines (Chen et al., 2012); the point that should be made here is that the immunosuppressive action of CBD and THC is in no way related to the immunosuppressive action of drugs such as methotrexate or cyclophosphamide. These drugs alter immunity as suppressors only, while CBD and THC modulate the immune response either by suppressing or by enhancing it, depending on the level of existing T-cell activation (Chen et al., 2012). These findings apply to HIV infections and it remains to be proven if they apply to other coronaviruses as well; nevertheless, some data are available: In SARS-CoV infections (very similar to current SARS-CoV-2), a severe decrease in circulating T-cells was observed in the acute phase (Channappanavar et al, 2014) and Giamarellos-Bourboulis et al (2020) have noted the same for SARS-CoV-2. It is, therefore, possible and worth investigating that the two basic phytocannabinoids, namely CBD and THC, would be indicated for the treatment of the acute phase of COVID19. CBDa, the acidic precursor of CBD, is known to have even more potent anti-inflammatory properties, in particular as a COX-2 inhibitor (Takeda et al, 2008).

Bibliographical evidence suggests that CBD has multiple modes of anti-inflammatory action, very comparable to colchicine (Drugs.com), save the serious adverse side effects (Leung et al, 2015); it is therefore only reasonable to have it tested on COVID19 patients for the prevention or treatment of the cytokine storm. THC should also be tested, since some preclinical evidence suggests it is useful in preventing the equivalent of ARDS in mice (Rao et al, 2015).

Overall, phytocannabinoids manifest their effect by directly suppressing effector T-cells, and by inhibiting kinase cascades and transcription factors leading to the production of pro-inflammatory molecules. One such example is the inhibition of phosphorylated p38, which leads to a decrease in the functionality of the inflammatory transcription factors AP-1 and NF-κB, thereby reducing inflammation. As mentioned earlier, miRNA-induced inflammation (Umbrello et al, 2016, Juknat et al, 2019) is not amenable to corticosteroid treatment, but is responsive to CBD and THC (Umbrello et al, 2017). This is another line of research, very much worth pursuing. Furthermore, most miRNA and long non-coding RNA (lncRNA) precursors were dramatically altered in THC treated mice, some down-, and others up-regulated. Yang X. et al (2019) explicitly state that a unique finding of their study on an animal model of autoimmunity was that the expression of many miRNAs and lncRNAs was dramatically and complexly affected by CBD. In other studies, THC treatment caused alternative promoter gene expression and splicing. The functions of those altered transcripts were mainly related to immune response and cell proliferation (Yang Y. et al, 2016).

In particular, the aforementioned actions of phytocannabinoids are manifested by the inhibition of the production and/or activity of important inflammatory cytokines such as, IFN-γ, IL-6, IL-1β, IL-2, IL-17A, TNF-α (mediated through enhancement of endogenous adenosine signaling (A2A receptors) (Nichols & Kaplan, 2020, Carrier et al, 2006), and chemokines such as CCL-2, which attracts monocytes, T-cells and dendritic cells to areas of inflammation. CBD, with its inhibitory effect on cryopyrin (NALP3), inhibits macrophage inflammasome activation, and thus the caspase-1 cascade is not activated or, were it activated, it would be controlled (Han & Mallampalli, 2015, Libro et al., 2016). Two pro-inflammatory interleukins, IL-1β and IL-6, are emerging as the decisive factors that dictate whether a COVID19 case will evolve into ARDS (through the combination of macrophage activation syndrome and immune dysregulation [Hellenic Institute for the Study of Sepsis, 2020]) or will self-cure. IL-1β is responsible for 25% of cases, while IL-6 for 75% (Giamarellos-Bourboulis et al., 2020). Interestingly, they are both mitigated by CBD (Nichols & Kaplan, 2020). There is less evidence for THC (Kozela et al, 2010, Keen et al, 2014, Eisenstein & Meissler, 2015). The problem of an autoimmune flare-up in the course of uncontrolled ARDS, uncontrollable with GCs, has been mentioned above (Burbelo et al., 2010). Phytocannabinoids are of known value in autoimmune conditions, but, to our knowledge, they have not been tried for this particular complication. Given this body of knowledge, not testing CBD and other cannabinoids as preventive of, and/or remedial agents for ARDS in the context of COVID19 might even be considered unethical.

Besides, cannabidiol directly suppresses inflammatory immune cells by up-regulating the IκB kinase complex, which inhibits the activity of the NF-κB transcription factor (Nichols & Kaplan, 2020). CBD also plays a regulatory role in inflammation by triggering the production of Treg and MDSC (Myeloid-Derived Suppressor Cells) (Dhital et al, 2017), as is the case in simple respiratory viral diseases, especially during the early phase. Apart from this, CBD exerts an immuno-apoptotic effect (ie withdraws inflammatory immune cells by the programmed cell death mechanism that is called “apoptosis”), as well as an apoptotic activity on infected cells; both actions appear to be important in controlling the degree of inflammation and the progression of infection (Nichols & Kaplan, 2020).

All the above actions of CBD are related to the suppression of innate (primary) immunoreactivity, the part that is extremely useful at the beginning of viral infections, but becomes harmful when it eventually gets out of control in the course of the disease: In high-risk groups, it might mitigate the tendency towards ARDS by calming the primed inflammasomes and the cytokine storm, but could also lead to a protracted viral disease.

In addition to treating uncontrolled inflammation in the context of viral disease in general, cannabinoids cause significant changes in epigenetic mechanisms (D’Addario et al, 2013), including methylation, histone modification, and non-coding RNA. The epigenetic regulation of viral infections through cannabinoids has received considerable attention in the literature, but this line of knowledge is not fully understood yet. With the increased methylation of host DNA under the influence of cannabis and methylating agents, the expression of many genes may be inhibited, and in particular of the genes related to cell-virus interaction, i.e., genes governing the entry of the virus into the cell, its structural integration, its output and subsequent inflammation (Tahamtan et al, 2016).

Based on the above theoretical/bibliographical data, CBD should be well suited for the exacerbation stage of COVID19 infection, for exactly the same reasons as colchicine, which has already begun to be administered experimentally. The only difference is that, unlike colchicine, CBD is free of important adverse effects. By the same token, its use as a prophylactic should be discouraged; the same applies to the initial phase of the infection: Full capacity of innate immunity is what is required initially. CBD could also prove very useful in the third phase of the infection, where the process of lung fibrosis starts. Concerning patients that already use CBD for other conditions; given the fact that immunosuppression is dose-dependent, they should probably keep using it during the epidemic, but in small doses, arbitrarily estimated at less than 15mg/day in divided doses. If larger doses are needed, and to let one err on the safe side, then CBD combined with strict social distancing should suffice. Smoking and vaping should be discouraged altogether (Williams, 2020).

Note: In the literature, CBD and THC are considered as isolated substances, thus without the notorious “entourage effect” of preparations from whole plants (Russo, 2018). The main exception is a few studies with AIDS/HIV patients, who were also users of smoked cannabis. There is a possibility that the use of whole spectrum oils would have a different effect on the immune response to viruses. The importance of several terpenes and flavonoids has been mentioned above (see healthy diet). These agents occur in abundance in cannabis and other plants, they are considered as GRAS (Generally Recognized As Safe) by the FDA, and they can also be used together with cannabis oils as supplements in an attempt to reconstitute the “entourage effect” of the whole plant. Special mention should be made for β-caryophyllene (BCP), which, besides being a partial CB2R agonist, exerts its anti-inflammatory action via inhibiting the main inflammatory mediators, such as iNOS, IL-1β, IL-6, TNF-α, NF-κB, COX-1, COX-2 and as a PPAR-α and PPAR-γ receptor agonist (Francomano et al., 2019), at least two of which are of cardinal importance in COVID19 ARDS.

9. Proposed drug combinations, based on computational network analysis

In order to minimize the translational gap between preclinical testing and clinical outcomes, Dr. F. Cheng of Cleveland Clinic devised a novel, integrative, antiviral drug repurposing methodology implementing a pharmacology-based network medicine platform, quantifying the interplay between the HCoV–host interactome and drug targets in the human protein-protein interaction network (Zhou et al., 2020). They came up with three pairs of existing drugs with a high probability of proving effective in subsequent clinical trials:

· Sirolimus, a mTORC1 inhibitor, plus actinomycin-D, an RNA synthesis inhibitor

· Mercaptopurine, a selective inhibitor of SARS-CoV and MERS-CoV that targets papain-like protease, plus melatonin, a biogenic amine that indirectly regulates ACE2R expression through inhibition of calmodulin

· Toremifene, a selective estrogen receptor modulator, plus emodin, an antiviral anthraquinone

These are predicted potential treatments that need clinical validation. This study attempts to speed up the development of treatment strategies for the COVID-19 pandemic.

Conclusions

In conclusion, the present author shares the view that, given our genome, proteome, etc, few new drugs with manageable adverse effects are possible. Instead of feverishly researching for drugs with names ending in –vir, -ab and –ib, maybe we should give a chance to existing drugs, with well-known and acceptable adverse effects; all we have to do is look for more intelligent ways to use and/or combine them, while at the same time not neglecting public measures, like building robust primary care systems, fighting poverty, and measures to improve the general health of the society, like promoting healthy nutrition including micronutrient supplementation, at least for those malnourished. Modern medicine should not be biased against repurposing time-honored substances like melatonin, chloroquine, etc, nor against previously miscategorized substances, like cannabinoids. We propose that drugs like melatonin, cannabinoids, estrogens, spironolactone, chloroquine (and similar), colchicine, acetaminophen, alone or in combinations, be given a fair chance to prove if and what they can do for us in this unfortunate conjuncture.

Summary

The purpose of the present article is to assess the COVID19 pandemic from an integrative perspective. SARS-CoV-2 is a novel coronavirus of still not fully traceable origin that took the World unawares. It is highly contagious, has a rather long incubation period and runs asymptomatic in a yet not known proportion of the population, especially in children; the world pandemic has unprecedented socio-economic consequences, related to social shut-down, elected by most governments as an effective epidemiologic measure, given the absence of “herd” immunity, and the unavailability of a vaccine and/or an effective treatment. Symptoms are practically indistinguishable from those of usual flu-like syndromes. Its course is benign in the vast majority of cases but the elderly and people with certain pre-existing morbid conditions tend to become severely ill and even die. The unfavorable course is usually introduced with un-noticed generalized immune dysregulation accompanied by difficulty breathing, rapidly evolving into acute respiratory distress syndrome (ARDS), possibly evolving into multiple systems failure and death. The immune dysregulation is introduced by a sudden increase of IL-1β or IL-6, usually between days 5 and 7 of the disease. The common element of comorbidities underlying unfavorable outcomes is a pre-existing low-grade inflammatory state. The virus enters the cell by attaching its cleaved spike protein to the receptor of angiotensin-converting enzyme (ACE2R) residing in the cellular membrane. Based on the above, the prevailing opinion that “we do not know enough to fight it” seems more as an agnostic’s postulation than a scientifically justified premise. What is really meant by this, is that we do not fully understand some specifics of the infection and its epidemiology, and we do not have a vaccine and a specific anti-viral drug. Such lack of exact and complete knowledge is common in medicine, and it need not paralyze society; we do know a lot of things, like general epidemiology, immunology, plenty of pharmacology, and so on, in such detail that allows us to act proactively.

We present a strategy for reduction of epidemiologic and personal risk, including public health measures, and measures for improving general health; the pros and cons of specific prophylactic measures, including vitamins, minerals and hormones, is discussed; therapeutic means for acute respiratory infections in the era of COVID19, including popular phytotherapeutics, are also discussed; several possible measures for the severely ill are proposed, including glucocorticoids, anti-sera, measures to counter the ill effects of cell-free hemoglobin, the time-honored drugs chloroquine and colchicine, estrogens, spironolactone, and off-label drug combinations proposed through advanced computational network analysis.

In conclusion, the present author shares the view that, given our genome, proteome, etc, few new drugs with manageable adverse effects are possible. Instead of feverishly researching for patentable expensive drugs with names ending in –vir, -ab and –ib that will only amplify existent inequality, maybe we should give a chance to existing drugs, with well-known and acceptable adverse effects; all we have to do is look for more intelligent ways to use and/or combine them, not neglecting public health measures and horizontal measures to strengthen innate immunity of the population. Modern medicine should not be biased against repurposing time-honored substances like melatonin, chloroquine, etc, nor against previously miscategorized substances like cannabinoids.

Conflict of interest

The author does not receive any remuneration from any source except his salary.

Funding

There was no funding for this study

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