In Anticipation of a Highly Virulent SARS-CoV-2 Variant–An ADDENDUM

In Anticipation of a Highly Virulent SARS-CoV-2 Variant:

An ADDENDUM

Rob Rennebohm, MD

September 15, 2023

Honore Daumier

This article represents an extended ADDENDUM to an earlier article entitled: In Anticipation of a Highly Virulent SARS-CoV-2 Variant:

https://notesfromthesocialclinic.org/in-anticipation-of-a-highly-virulent-sars-cov-2-variant/

The purpose of both articles is to provide information that might help the general public, health care professionals, and health departments to optimally prepare for the potential arrival of a highly virulent SARS-CoV-2 variant.

INTRODUCTION:

As Dr. Geert Vanden Bossche (GVB) has explained in his thoughtful scientific analysis of the COVID-19 mass vaccination campaign—see his book, The Inescapable Immune Escape Pandemic and my review of his analysis: https://www.trialsitenews.com/a/how-has-the-covid-19-mass-vaccination-campaign-made-the-natural-selection-and-rapid-propagation-of-a-highly-virulent-variant-highly-likely-44952cc7—he is deeply concerned that:

The COVID-19 mass vaccination campaign, which was implemented in the midst of an active pandemic, has placed great sub-optimal¹ population-level immune pressure on the SARS-CoV-2 virus.

¹Note: An “optimal” vaccine is one that induces sterilizing immunity in the vaccinee, such that the virus is killed (i.e., becomes unable to replicate and spread to others) when the vaccinee subsequently encounters the virus. When a sufficiently high percentage of the population develops sterilizing immunity to a particular virus (e.g. 75% of the population in the case of some epidemics/pandemics), herd immunity is achieved and the epidemic/pandemic ends, because the virus runs out of accessible, susceptible new hosts. A “suboptimal” vaccine is one that induces immunity that may thwart viral replication and transmission but does not adequately prevent viral replication and transmission, and thereby allows the virus to survive and spread. The COVID-19 vaccines are suboptimal vaccines—they do not result in sterilizing immunity, they do not result in killing of the virus, they do not prevent infection or transmission, and therefore they do not contribute to herd immunity. In fact, they interfere with development of herd immunity. At best, COVID-19 vaccination may temporarily reduce disease severity (reduce hospitalizations and death).

This suboptimal population-level immune pressure is responsible, predictably, for the natural selection and dominant propagation of a vast array and continuing succession of increasingly infectious new “immune escape” variants—e.g. the many Omicron variants.
The immune status of heavily vaccinated individuals (those who have received an initial series and additional booster doses,) has become abnormal, particularly if the vaccinated individual did not experience productive natural SARS-CoV-2 infection prior to their vaccination. (“Productive” natural infection means the person became naturally infected and mounted a significant and appropriate immune response to that infection). The immune system of heavily vaccinated individuals has needed to do things it normally has not needed to do (e.g., produce high levels of protective virulence-inhibiting PNNAbs² and substantial levels of SIR³-created broadly neutralizing antibodies) and has become less able to do things it normally needs to do (e.g., its cell-based innate immune system has been sidelined, unable to optimally participate in viral clearance and unable to contribute to the development of sterilizing immunity).
The suboptimal population-level immune pressure will inevitably (and soon) lead to the natural selection and rapid propagation of an immune escape variant (or variants) that is able to overcome the key virulence-inhibiting measure that the immune system of vaccinated individuals has been using to protect vaccinees from severe disease and death—namely, virulence-inhibiting PNNAbs (polyreactive non-neutralizing antibodies).
This highly virulent SARS-CoV-2 variant will have great potential to cause severe illness and death, particularly in heavily vaccinated individuals, particularly in highly (and rapidly) vaccinated countries, particularly if the vaccinated individual did not experience productive natural SARS-CoV-2 infection prior to their vaccination, especially if the vaccinated individual is elderly and has co-morbidities.

The general public and their physicians have a right to know about GVB’s concerns, analysis, and conclusions so that they can proactively prepare for the highly likely arrival of a highly virulent variant. It is in that spirit that the following anticipatory thoughts and suggestions are offered.

²Note: PNNAbs = Polyreactive non-neutralizing antibodies. The virulence-inhibiting effect of PNNAbs is due to the following: During an acute viral respiratory infection (like SARS-CoV-2 infection) virus is typically adsorbed onto (becomes tethered to) the surface of patrolling migratory dendritic cells (a type of immune cell), which then carry the virus from the upper respiratory tract (URT) down to the lower respiratory tract (LRT) and potentially to other internal organs. Upon arrival in the LRT, these virus-laden dendritic cells may then transfer the virus to epithelial cells in the LRT, thereby infecting those cells, which in turn infect neighboring epithelial cells, resulting in potentially severe LRT infection. This is referred to as “trans-infection” of the LRT.

PNNAbs are able to bind to virus that is tethered to these migratory dendritic cells. When PNNAb is bound to tethered virus, the virus is not easily released from the dendritic cells and cannot easily trans-infect epithelial cells in the LRT. In this way, PNNAbs are “virulence-inhibiting” and thereby protect against severe infection in the LRT and other internal organs (i.e., protect against severe disease and death). The virulence of an anticipated “highly virulent variant” is anticipated to be due to the ability of the variant to overcome (become resistant to) the virulence-inhibiting effect of the PNNAbs. That is, the PNNAbs will not be able to prevent the highly virulent variant from trans-infecting cells in the LRT. Accordingly, severe disease in the LRT will result.

³Note: SIR = Steric Immune Refocusing. In the context of SARS-CoV-2, SIR refers to the redirection (refocusing) of the immune system to produce neutralizing antibodies against conserved immune-subdominant epitopes of the spike protein when pre-existing poorly neutralizing (out-of-date) antibodies sterically hinder (physically block) immune recognition of the variable immune-dominant epitopes of the spike protein. Vaccinated individuals, via the SIR phenomenon, produce broadly reactive neutralizing antibodies to immunosubdominant spike-associated domains. These SIR-created high avidity antibodies have temporarily provided efficient cross-neutralizing activity. These SIR-created antibodies partially compensate for the ineffectiveness of obsolete (out-of-date) vaccine-induced neutralizing antibodies (e.g. the vaccine-induced neutralizing antibody to the now extinct Wuhan strain of SARS-CoV-2).

A BRIEF REVIEW OF THE USUAL CLINICAL COURSE OF SEVERE COVID-19—AT LEAST UP UNTIL NOW:

To date, the clinical course of severe COVID-19 has typically had two major phases—an initial acute viral phase (typically lasting 7-10 days) followed by a hyperimmune phase, which has usually become clinically apparent after day 7 and increases during the second and third weeks of the illness. The hyperimmune phase is due to an intense and dysregulated “hyper” immune reaction to the virus and is characterized by varying degrees of “cytokine storm” and associated inflammation within the lower respiratory tract (LRT) and potentially in other internal organs. By the time the hyperimmune phase has become clinically apparent, the viral load may have already greatly diminished—due to adequate clearing, even complete eradication, of the virus by that time (thanks to the immune system and help from anti-viral therapies and nutraceuticals, if those therapies are given)—but such diminution of viral load is not always the case. The worst imaginable scenario would be a combination of an extremely high and undiminishing viral load and an extraordinarily intense hyperimmune reaction.

Fortunately, most people who develop COVID-19 do not develop severe COVID-19. Instead, they experience only an acute viral phase (without a clinically apparent hyperimmune phase), or they develop only a mild to moderate hyperimmune phase, at most. They are able to eradicate the virus (or at least greatly diminish the viral load) within 7-10 days, and they ultimately have a good outcome.

To date, most patients with severe COVID-19 who end up in the ICU (typically during the second or third weeks of the illness) and die from their COVID-19 do so primarily because of an extraordinarily severe and damaging hyperimmune phase (with severe cytokine storm). In such patients, secondary bacterial infection of the lungs can be a complicating factor, as can abnormal thrombosis.

ANTICIPATORY QUESTIONS:

In anticipation of the possibility that a highly virulent variant may emerge and rapidly propagate, several questions need to be raised and addressed, now:

When/if a highly virulent variant arrives, who will be most affected, who will be least affected, and why?
How will the illness it causes behave? What is the spectrum of possibilities?
How severe will the illness be?
How quickly (after onset of symptoms) will peak severity of illness occur?
How overwhelming will the acute viral phase be and how long will the acute viral phase last?
In what percentage of patients will there be a hyperimmune phase (e.g., “cytokine storm”), how severe will it be, how soon will it occur after onset of symptoms, to what extent will it reduce viral load (i.e. be helpful), to what extent will it be harmful?
How effectively will the human immune system be able to respond to this variant?
Will the efficacy of the immune response and the severity of illness depend on vaccination status?
How can the clinical course of the illness be best monitored and interpreted?
What are the indications for early introduction of anti-viral therapy during acute SARS-Co-V-2 illness? What other early treatments may be helpful?
What anti-viral therapy has the most favorable benefit/risk ratio?
How is the hyperimmune phase/”cytokine storm” recognized and best managed?
How is the threat of COVID-19-related thrombosis best managed?
What is the role of home use of pulse oximetry?
How can COVID-19 home antigen tests and COVID-19 PCR tests be optimally utilized?
Is there a role for prophylactic anti-viral therapy and prophylactic use of nutraceuticals?

Who will be at greatest risk for hospitalization and death? There is a spectrum.

When/if a more virulent variant arrives, there is a spectrum regarding the extent to which a given infected individual is at risk for severe disease and death:

According to GVB’s analysis, the status of a heavily vaccinated individual’s immune system is worrisomely different from the normal status of the immune system of healthy unvaccinated individuals. As stated earlier, the immune system of vaccinated individuals has needed to do things it normally has not needed to do (e.g., produce high levels of protective virulence-inhibiting PNNAbs and substantial levels of SIR-created broadly neutralizing antibodies) and has become less able to do things it normally needs to do (e.g., its cell-based innate immune system has been sidelined, unable to optimally participate in viral clearance and unable to contribute to the development of sterilizing immunity).

In contrast, the immune system of an unvaccinated individual has been left intact—-e.g., it has not needed to rely on virulence-inhibiting PNNAbs or SIR-created antibodies; its innate immune system has not only remained intact, but it also has become increasingly trained, practiced, and experienced during the COVID pandemic, particularly during the Omicron era; and its adaptive immune system is able to normally react and adjust to new variants. Whereas unvaccinated individuals develop sterilizing immunity after infection and thereby contribute to herd immunity, COVID-19 vaccination does not result in sterilizing immunity and thereby does not contribute to herd immunity.

Not only has the COVID-19 mass vaccination campaign adversely affected the immune system of the vaccinated individual, but also the altered immune status of vaccinated individuals, collectively (i.e., at a population level), has placed great sub-optimal population-level immune pressure on the virus, causing the virus to evolve in unusual ways. Indeed, the mass vaccination campaign has been responsible for the natural selection and dominant propagation (or co-circulation) of a continuous succession and vast array of increasingly infectious “immune escape” variants. This vast and increasing array of successively dominant variants would not have occurred in the absence of the mass vaccination campaign.

The virulence-inhibiting effect of vaccinees’ PNNAbs will ultimately become suboptimal and put population-level immune pressure on the virus such that a variant that is capable of overcoming that effect will have a competitive advantage, will become naturally selected, and will rapidly propagate. This new variant will be highly virulent when it infects heavily vaccinated individuals, who have been depending on the virulence-inhibiting effect of PNNAbs to prevent severe disease and who otherwise have an adversely altered immune status. In comparison, healthy unvaccinated individuals, who have normally performing immune systems and have not been relying on virulence-inhibiting PNNAbs, will be far less affected by this variant. In other words, this variant that threatens to be “highly virulent” when it infects heavily vaccinated individuals will be much less threatening to healthy unvaccinated individuals.

Accordingly, when this “highly virulent” variant arrives (is naturally selected and rapidly propagates in a given community), heavily vaccinated individuals will be at greatest risk of severe disease and death, and young healthy unvaccinated individuals will be at least risk. There is no guarantee that healthy unvaccinated individuals will be able to handle this more virulent variant well, but they will be much better equipped to do so than will the heavily vaccinated.

The immune system of a heavily vaccinated individual—particularly if the individual did not experience productive natural infection prior to vaccination, especially if the individual is elderly and already unhealthy with co-morbidities—will have great difficulty meeting the challenge of a highly virulent variant and will need lots of medical help and support. Although their COVID-19 vaccination, to date, has provided protection against severe disease and death—thanks largely to the virulence-inhibiting effect of PNNAbs (as well as other temporarily helpful but unstable, unsustainable, and ultimately harmful immune adjustments)—this effect will no longer be available to vaccinated individuals once a highly virulent variant arrives, because the virulence of this variant will primarily be due to its ability to overcome the virulence-inhibiting effect of the PNNAbs.

So there is a spectrum regarding the risk of severe disease and death when/if a highly virulent variant appears on the scene. At one end of the spectrum are individuals who have been heavily vaccinated (have received an initial series and additional booster doses), were vaccinated prior to developing productive natural infection, and are elderly and have co-morbidities. At the other end of the spectrum are young healthy unvaccinated individuals who, to date, have had considerable experience with Omicron variants. There is a broad spectrum of risk between these two extremes. People who experienced definite productive SARS-CoV-2 infection prior to receiving COVID-19 vaccination should be much better off than people who were vaccinated prior to ever experiencing natural infection. Natural infection prior to vaccination provides at least some training of the cell-based innate immune system and possibly some priming of the adaptive immune system, and such individuals may be able to draw on that training to at least some extent. People who received only one dose of vaccine (en toto) will be better off than those who received 2 or more doses.⁵ Those who received only two initial doses of vaccine (and no booster doses) will be better off than those who have been heavily vaccinated (with 3 or more doses). The fewer total doses, the better.

⁵Note: Healthy vaccinees who only received a single injection of an mRNA-based COVID-19 vaccine or no more than 2 injections with a non-mRNA-based vaccine prior to developing a symptomatic vaccine-breakthrough SARS-CoV-2 infection are thought to have preserved their capacity to train their cell-based innate immune system.

Risk also depends on how “immunologically reactive” a vaccinated person’s immune system was to their vaccination. If their immune system was only minimally (or not at all) reactive to their vaccine dose(s) (i.e., they did not experience a good “take” or “response” to the vaccine) they will be better off than someone whose immune system was very reactive to their vaccination. And, of course, there is a spectrum of immune reactivity between these two extremes.

There have been concerns (backed by data) that not all “batches” of vaccine have been equal. Some batches might have a greater quantity and/or quality of mRNA than other batches of the “same” product, due to serious quality control issues. A person will be better off if their vaccination was with a dose from a less potent, lower-quality batch. The Pfizer mRNA vaccine has had 30 micrograms of mRNA, compared to 100 micrograms in the Moderna vaccine. It is unclear whether this larger amount in the Moderna vaccine is a risk factor. It is likely that people who have been vaccinated with a non-mRNA vaccine will be better off than those who received mRNA vaccines.

Risk also depends, of course, on the overall state of health of a person. People who are young, physically fit, well-exercised, well-nourished (including having solidly normal Vitamin D levels), emotionally healthy, and do not have co-morbidities will be much better equipped to handle a highly virulent variant than elderly individuals who are without these healthy characteristics. And, of course, there is a spectrum of general health status between these two extremes.

How will illness due to a highly virulent variant most likely behave and how will it need to be treated? It largely depends on the immune status of the infected individual.

There is a spectrum regarding how the illness (caused by a highly virulent variant) will unfold in a given individual and how it will need to be treated. It will depend primarily on the vaccination status of the individual (as discussed above) but also on the other general health factors mentioned. Since this represents uncharted territory, it is unknown exactly how the illness will behave and unfold. Below is my best guess. I offer it not with any claim that it is certainly correct, but to stimulate and facilitate proactive scientific dialogue and thoughtful anticipatory planning regarding how illness due to a highly virulent variant might behave and how it might be best monitored, treated, or prevented in the first place.

In the case of heavily vaccinated individuals (particularly if they are elderly and already unhealthy with co-morbidities, especially if they did not have productive natural infection prior to vaccination) we should be prepared for the possibility that the illness will unfold as follows:

Because their immune system will have very little capacity (at either the cell-based innate immunity level or the adaptive immunity level) to control the virus, they will quickly become overwhelmingly infected, in the upper respiratory tract (URT), lower respiratory tract (LRT), and possibly other internal organs. They might have very high viral loads in all of these locations. Unfortunately, they will not be able to rely on usual immune mechanisms to control the virus—e.g., NK cells (natural killer cells, which are a key component of the cell-based innate immune system) or on effective utilization of their adaptive immune system. The acute viral phase of their illness may therefore quickly become extraordinarily severe and may last more than the usual 7-10 days. Their immune system may resort to the most primitive, non-specific, and violent of its rapid response mechanisms—-namely, macrophage activation and massive release of cytokines from these macrophages, i.e., desperate production of a massive “cytokine storm.”^6,7 But even this desperate effort may fail to even partially control the virus.

⁶Note: Although the cell-based innate immune system (e.g., NK cells) in heavily COVID-19 vaccinated individuals is sidelined, cytokine production by the innate immune system is not sidelined.

⁷Note: For more information about “cytokine storm” and its treatment (both in COVID-19 and in other clinical situations), see the following article: Treatment of Severe COVID-19: https://notesfromthesocialclinic.org/treatment-of-severe-covid-19-illness-long-version/

The best hope for the above-mentioned high risk patients will be prophylactic anti-viral treatment (initiated well before exposure to the more virulent variant) in an effort to prevent them from developing infection with a highly virulent variant in the first place. (We will return to prophylactic treatment considerations later.) But if such high risk patients do become ill with a virulent variant (either in the absence of prophylactic anti-viral treatment or despite it), their best hope will be prompt initiation of an optimal therapeutic dose of anti-viral therapy as soon after onset of symptoms as possible. However, if that anti-viral therapy is inadequately effective and they experience “cytokine storm,” their next best hope is that the cytokine storm will somehow bring the virus under some semblance of control—without the cytokine storm causing severe damage to the patient in the process.

To be effective, this cytokine storm may need to be launched by the immune system early during the course of the overwhelming viral infection, particularly if anti-viral therapy is inadequately effective—-probably within the first 1-3 days after onset of COVID-19 symptoms (as opposed to starting on day 8 or later, which has been the case with severe COVID-19 to date). Instead of a cytokine storm occurring in only a small percentage of patients (which has been the case with COVID-19 to date) and typically occurring only after day 7, a cytokine storm will likely occur in a high percentage of high risk patients and will likely occur 1-3 days after onset of symptoms. In other words highly vaccinated high risk patients will end up in the ICU within the first week of their illness rather than during the second or third week, and a higher percentage of them will end up in the ICU.

There is a fine line between the cytokine storm being helpful and being harmful. Although the cytokine storm might initially help control the virus infection, the cytokine storm will quickly become organ-threatening and life-threatening because of the massive inflammation and harmful cascading problems it can create.

This combination of overwhelming viral infection and massive cytokine storm, occurring in rapid succession (even simultaneously) early in the course of the illness (during the first week, even early during that week) creates a difficult therapeutic dilemma for the hospitalists or ICU physicians. On the one hand, the patient is suffering from overwhelming viral infection (with a high viral load); on the other hand, the patient is experiencing a potentially life-threatening cytokine storm that may or may not be able to reduce the viral load. Complicating matters is the fact that the anti-viral therapy that should be administered as early as possible, may or may not be adequately effective.

Under the above circumstances, the physician will need to quickly estimate the patient’s viral load (at a given point in time and serially thereafter), quickly determine whether (and to what extent) the patient (at that same moment in time) is experiencing a cytokine storm, and decide whether that cytokine storm is doing more harm than good (or vice versa). In addition to providing anti-viral treatment, the physician will need to decide whether and when to protect the patient from life-threatening damage potentially (and likely) wrought by the cytokine storm. Ideally, this decision should be informed by prospectively and serially collected clinical data (on the given patient) regarding the extent to which the anti-viral therapy and/or cytokine storm have reduced the viral load (not just in the URT but also in the LRT) and the extent to which the cytokine storm is beginning to cause more harm than good. The best available way to estimate the viral load would be to prospectively follow serial PCR tests (paying close attention to Ct values at which a test is positive), initially in the URT, but soon, if indicated, in the LRT (by swabbing bronchial mucosa). (See discussion of Ct values below.) The best way to serially monitor the intensity and course of the cytokine storm and the threat it is posing is to serially follow serum ferritin levels, CBC, ESR, CRP, liver function tests, d-Dimer, etc. Serial serum ferritin levels are particularly helpful. We would like to see initially high ferritin levels substantially and quickly falling towards the normal range.

The temptation on the part of the physician will be to withhold immunosuppressive treatment of a harmful cytokine storm out of concern that such treatment might interfere with the potential anti-viral effect of the anti-viral medication and/or the anti-viral effect of the cytokine storm. However, if treatment of the cytokine storm (with high dose corticosteroid and anti-cytokine therapy, such as anakinra or tocilizumab) is delayed for too long, the risk of severe organ damage and death from cytokine storm, with or without concomitant overwhelming viral load, rapidly increases.

It may prove best to give anti-viral treatment and initial cytokine storm at least a brief chance to at least partially control the virus, but be prepared to quickly shift to prioritizing anti-cytokine storm therapy as soon as an adequate decrease in viral load has occurred or as soon as it becomes apparent that the cytokine storm can no longer be left inadequately treated. This will be a difficult and uncomfortable decision. In an individual patient the relative risk of treating cytokine storm versus the risk of not treating cytokine storm is difficult to discern and may be equal. Serial testing of viral load (in the URT and, if indicated, in the LRT) and serial monitoring of the cytokine storm will be helpful and critically important. Careful and frequent monitoring and repeated re-evaluation of the patient will be essential. A balanced, titrating approach, based on frequent reassessments will be key. It will be necessary to be both appropriately bold and appropriately cautious. It may not be possible to save some patients, even with best possible decision-making.

Bear in mind that it is quite possible that the cytokine storm triggered by the highly virulent variant in high risk heavily vaccinated individuals will be more massive and explosive than has ever been seen in many adult ICUs. The cytokine storm might require extraordinarily high doses of anakinra, e.g., and a very large number of patients might need such treatment. Accordingly, an important anticipatory step (to be taken now) would be to ramp up global production of anakinra (as well as tocilizumab and IV methylprednisolone) so that all patients who need these medications will have prompt access to them.

It is highly likely that current global supplies of anakinra and tocilizumab are woefully inadequate to meet the need that may occur when a highly virulent variant arrives. It would be a shame if the supply of these medications falls short of the need for them. Also, to date (i.e., historically), the prices charged for anakinra and tocilizumab have been exorbitant. It would be a shame if the price for anakinra and tocilizumab results in these medications being unaffordable for treatment of cytokine storm triggered by a highly virulent variant. Production of anakinra and tocilizumab, therefore, needs to be immediately and greatly ramped up (at “warp speed”) and the price of these medications needs to be immediately ramped down!!

Management of most healthy unvaccinated patients will likely be much less difficult. They will be better able to handle the highly virulent variant and will be less likely to develop cytokine storm. Although the “highly virulent variant” will, indeed, be highly virulent in high risk heavily vaccinated individuals (because the immune status of heavily vaccinated individuals has been altered by the mass vaccination campaign and they have been depending on virulence-inhibiting PNNAbs, which the highly virulent variant is able to overcome), the “highly virulent variant” will not be as virulent in healthy unvaccinated individuals (because their immune systems will be intact and able to respond in a normal way, and they have not been depending on virulence-inhibiting PNNAbs). As explained earlier, the immune status of heavily vaccinated individuals has become abnormal and is now quite different from the normal immune status of healthy unvaccinated individuals.

When the highly virulent variant arrives, it is appropriate to hope that the illness it will cause in healthy unvaccinated individuals will usually resemble the mild-moderate cases of COVID-19 that were typical during the first 3.5 years of the pandemic. But there is no guarantee that unvaccinated individuals (particularly those who are elderly and/or have co-morbidities) will experience only mild-moderate illness. We need to be prepared for the possibility that some unvaccinated individuals, particularly elderly individuals with co-morbidities, may become severely ill and may need the same excellent clinical care that heavily vaccinated individuals may need.

In between these two extremes (a rapid life-threatening course in the high-risk heavily vaccinated and a less severe course in the healthy unvaccinated) will be a spectrum of courses, with varying degrees and rapidity of viral clearance, varying incidence of problematic cytokine storm, and varying degrees (and timing) of cytokine storm. Monitoring and treatment will need to be patient-specific—i.e., individualized, according to a patient’s position along the spectra discussed above.

Is there a role for prophylactic anti-viral therapy?

Given the worrisome way in which illness due to a highly virulent variant is likely to behave, at least in the highest-risk heavily vaccinated, is there a role for prophylactic anti-viral therapy?

It seems appropriate to strongly consider prophylactic anti-viral therapy,^8,9 at the very least for people who are at particularly high risk of developing life-threatening illness when they contract the highly virulent variant. It is less clear whether prophylactic anti-viral therapy is appropriate for people at less risk. Prophylactic anti-viral therapy should be strongly considered for health care workers, including staff in retirement homes and nursing homes, to protect those workers and the people they serve. Prophylactic anti-viral therapy would be least important for young healthy unvaccinated individuals. However, in populations where the highly virulent variant is widely circulating, one could build a very strong case for encouraging prophylactic anti-viral treatment for virtually all people, including those who are healthy and unvaccinated—for the sake of protecting high risk patients. Such widespread prophylactic anti-viral therapy could substantially reduce the quantity of virus circulating in the population as a whole and, thereby, reduce likelihood of infection of the most vulnerable. In other words, young healthy unvaccinated individuals would not necessarily need or want to take prophylactic anti-viral medication for their own sakes, but they may choose to take prophylactic anti-viral medication in an effort to help protect the most vulnerable.

In addition to prophylactic use of anti-viral therapy, an important component of prophylactic protection is regular use of nutraceuticals to establish and maintain optimal levels of Vitamin D, Zinc, etc.

⁸Note: For purposes of this discussion, “anti-viral therapy” refers to therapies such as nirmatrelvir/ritonavir (Paxlovid), remdesivir, molnupiravir, ivermectin, and hydroxychloroquine—and not to nutraceuticals (vitamin D, Zinc, etc.)

⁹Note: Although the safety of prolonged prophylactic use of hydroxychloroquine has been well-established (e.g., for malaria and for control of lupus) and there has been considerable (and favorable) experience with prolonged prophylactic use of ivermectin for protection against COVID-19, there is no experience with prolonged (or even short term) prophylactic use of Paxlovid, remdesivir, or molnupiravir, regarding safety or efficacy, and, therefore, prophylactic use of Paxlovid, remdesivir, or molnupiravir cannot be recommended.

What are the indications for early introduction of anti-viral therapy during acute illness due to a highly virulent variant of SAARS-CoV-2?

Those who are at high risk for severe disease when infected with a highly virulent variant (e.g. the heavily vaccinated and those with co-morbidities) should be started on an optimally therapeutic dose of anti-viral therapy as early as possible when/if they develop acute illness—e.g. on day one, ideally. Early introduction of anti-viral therapy should also be strongly considered for healthy unvaccinated individuals when they become ill with COVID-19, particularly if the person is elderly and/or has co-morbidities. Early introduction of anti-viral therapy for virtually all people infected with the highly virulent variant might be strongly considered for one other important reason—-as a way to reduce the overall viral load in a hospital and community and thereby protect hospital workers, nursing home care givers, and the most vulnerable members of a community. In a community that is experiencing a great amount of circulating virus, treatment of all citizens (except for children?), regardless of whether they are ill, with a therapeutic dose of anti-viral therapy (for approximately 2 weeks or longer?) might be a consideration—in an effort to eradicate the virus from the community (or at least substantially reduce the amount of virus circulating in the community), again for the sake of protecting the most vulnerable.

What anti-viral therapy has the most favorable benefit/risk ratio?

The best way to determine which anti-viral therapy has the most favorable benefit/risk ratio would be to conduct a large, careful, high-quality, objective, honest, head-to-head study that compares all available anti-viral therapies for SARS-CoV-2—-for example, a comparison between Paxlovid, remdesivir, molnupiravir, ivermectin (IVM), and ivermectin plus hydroxychloroquine (HCQ). Unfortunately, despite the fact that we are nearing the end of the 4th year of the pandemic, and despite the obvious need for such a comparative study, no such study has been conducted. So, we do not have optimal comparative data regarding which of those five treatment options has the most favorable benefit/risk ratio.

When issues of conflict of interest, quality of data collection, honesty of data analysis, honesty of data presentation, quality and quantity of safety studies, issues of publication integrity, drug cost, and actual clinical and public health experience on the frontlines (e.g., in Mexico City, Uttar Pradesh, and Honduras) are taken into account, the anti-viral medication that appears to be most trustworthy and appears to have the most favorable benefit/risk ratio is not Pfizer’s Paxlovid or Merck’s molnupiravir or Gilead’s remdesivir, but ivermectin or the combination of IVM and HCQ.

In my opinion, IVM or IVM plus HCQ are the best options and have the most favorable benefit/risk ratio. Personally, I am impressed by the experiences that physicians in Honduras, Mexico City, Uttar Pradesh, and many other countries have documented with the Nobel prize-winning drug, ivermectin, which is a unique and truly extraordinary drug that has saved millions of people from the devastation of river blindness. Personally, I have been appalled by the unscientific and unethical ways in which promoters of the mass vaccination campaign have demonized ivermectin and have censored, belittled, ridiculed, and punished physicians for advocating treatment of COVID-19 with ivermectin. But, again, head-to-head comparative studies have not been done. If they were to be done, they would need to be performed according to the strictest of scientific and ethical principles. Sadly, during the COVID-19 pandemic, those fundamental principles have not been impeccably and uniformly practiced by the promoters of the prevailing COVID-19 narrative, as I have explained in several other writings—see: https://notesfromthesocialclinic.org/how-would-three-of-canadas-greatest-historical-figures-respond-to-the-covid-situation-if-they-were-alive-today Unfortunately, pharmaceutical companies have had grossly inappropriate influence and control over data collection, data analysis and the reporting of data.

For more information on scientific studies and recommendations regarding ivermectin and hydroxychloroquine, as well as the role of nutraceuticals and other treatments of COVID-19, the reader is referred to the following excellent websites and other sources of information:

FLCCC website: www.covid19criticalcare.com
Canadian COVID Care Alliance website: https://www.canadiancovidcarealliance.org/
McCullough Protocol: https://www.amjmed.com/article/S0002-9343(20)30673-2/fulltext
Interview with Honduran physician by Dr. Philip McMillan:
- https://streamyard.com/4q9fgua5cvem
- https://philipmcmillan.substack.com/p/why-was-the-covid-success-from-honduras?utm_source=substack&utm_medium=email&utm_campaign=email-half-post&r=10zdde#play

What is the role of anti-thrombotic treatment of COVID-19?

Abnormal clotting (including microvascular thrombosis as well as macrovascular thrombosis) can complicate COVID-19. This potential complication needs to be kept in mind throughout the course of the illness, because it can start developing early (during the first week), though it may not become manifest until later. Prospective, serial monitoring for thrombosis is, therefore, essential, starting with d-Dimer and platelet counts. Early treatment with aspirin (for its beneficial anti-platelet effect) may be appropriate. Early treatment with an oral anticoagulant (e.g. apixaban) might be indicated in some patients, including outpatients. Early treatment with heparin may be appropriate, especially for high-risk heavily vaccinated inpatients.

What other early treatments should be considered?

In addition to the already-mentioned treatments, several other “early treatments” can be considered: nutraceuticals (most importantly, Vitamin D, Zinc, Vitamin C, and Thiamine), azithromycin, famotidine, and fluvoxamine. Nasal sprays (with diluted povidone iodine) and mouth washes (e.g., with Scope) can be remarkably helpful. In some patients early treatment with colchicine (at the onset of suspected hyperimmune phenomena) and promethazine (at the onset of suspected pulmonary disease) may be appropriate. Antibiotic coverage for possible secondary bacterial infection of the LRT may also be needed. Please see the excellent websites mentioned above for specific details.

The role of pulse oximetry monitoring:

When a heavily vaccinated individual who is at particularly high risk of developing severe disease when infected by a highly virulent variant (e.g., elderly individuals with co-morbidities who were vaccinated prior to any productive natural infection) develops COVID-19, it would be wise to frequently use pulse oximetry to monitor the oxygen saturation in their blood. Pulse oximeters can be purchased in drug stores and used in one’s home. If an outpatient serially monitors their oxygen saturation with a pulse oximeter, starting soon after onset of symptoms, and the results remain stable in the normal range, this can be reassuring. If, however, serial monitoring reveals that oxygen saturation is dropping below the normal level, this would be cause for concern. Serial monitoring of oxygen saturation can greatly improve early detection of when/if a patient is developing potentially worrisome pulmonary disease—due either to severe viral infection in the LRT, or severe cytokine storm that is causing severe inflammation in the LRT, or micro or macro thrombosis within the lungs, or secondary bacterial infection in the LRT, or various combinations of these problems. People who are at less risk for severe disease may also want to monitor their oxygen saturation, primarily for reassurance.

Regarding COVID-19 PCR testing:

The COVID-19 PCR tests¹⁰ have usually been used to provide only a “positive” or “negative” result, not a quantitative result. If the test is positive, the extent to which it is positive (strongly, weakly, or in-between?) has not routinely been reported to the physician or patient. Although the COVID PCR tests were not specifically designed to indicate the quantity of virus present (viral load), they can be used to provide a rough estimate of the viral load—by paying attention to the Ct (cycle threshold) value at which a test became positive.

¹⁰Note: For detailed information about the COVID-19 PCR test, see the following article: The Importance of Knowing the Ct Value at which a COVID PCR Test is Positive: https://notesfromthesocialclinic.org/the-importance-of-knowing-the-ct-value-at-which-covid-pcr-tests-are-positive-long-version/

When a COVID-19 PCR test is positive, the Ct value represents the number of times the molecular material in the specimen needed to be amplified before it was possible for the testing machine to detect the presence of fragments of the SARS-CoV-2 virus. If only 10 cycles of amplification were needed, that would mean that there was an enormous amount of SARS-CoV-2 viral material in the specimen. If 20 cycles of amplification were needed, that would suggest that a large amount of SARS-CoV-2 viral material was present, but not an enormous amount. If 28 cycles of amplification were needed, that would correlate with presence of a small-moderate amount of the virus. If more than 32 cycles of amplification were needed to detect presence of possible SARS-CoV-2 viral material, the result, although “positive,” is not reliably interpretable—it may or may not mean that SARS-CoV-2 viral material is truly present, and even if the detected material is truly SARS-CoV-2 material, it could simply mean that a few fragments of dead virus were present. If the test does not become positive until 40, 45, or 50 cycles of amplification have been performed, such a “positive” result is inadequately interpretable, totally unreliable, and certainly could represent a “false positive.”

Unfortunately, most of the laboratories (at least in the USA) initially programmed their PCR testing equipment to stop looking for SARS-CoV-2 viral material only after 40 cycles of amplification had been performed. In other words, the test result was reported as negative only if the test was still negative after 40 cycles of amplification. Some labs have set their equipment to continue amplifying until 45 (or 50) cycles of amplification have been completed—a practice that surely generates many false positives.

If a COVID-19 PCR test is “positive,” it is important and helpful to know whether it was positive after only 10 cycles of amplification (i.e., at a Ct value of 10) or only after 40 cycles of amplification (at a Ct value of 40), or at a Ct value somewhere in-between (e.g., at a Ct value of 15, 20, or 25). Such information would provide at least a rough, but valuable, estimate of the viral load.

For example, if all residents in a nursing home were to undergo COVID-19 PCR testing and 20% of them were found to have a “positive” test, it would be important to know whether all of those positive tests were positive at a Ct value less than 28, or all of the positive results were positive only after 40 cycles of amplification (at a Ct value of 40). The latter result would not necessarily mean that any of those “COVID-19 positive” patients truly had COVID-19.

Likewise, if a professional basketball or football player tests “positive” before an important game, it would be important to know whether the “positive” test was positive at a Ct of 10 or 45. The latter result would be totally unreliable.

The above discussion points out how important it is to know the Ct value at which any “positive” PCR test had become positive.

The above discussion also reveals the value of serially following COVID-19 PCR results in a given patient (with disclosure of the Ct value of all positive tests). If, for example, a patient initially had a positive PCR test at a Ct of 10 (meaning that the patient was carrying a huge load of virus at that time), but two days later had a positive test at a Ct of 18, then 2 days after that the test was positive only at a Ct of 24, then 2 days after that the test was positive only after 35 cycles of amplification (meaning that there was little, if any live virus still present in the specimen, possibly just dead fragments, if that)—this would suggest that the patient was clearing the virus very well. On the other hand, if a given patient’s serial PCR tests are all positive at a Ct in the range of 16 and are showing no signs of improving, that would suggest that the patient is having difficulty clearing the virus.

What if a patient is on day 8 (or earlier) of their illness and suddenly becomes much more severely ill? Are they worsening because the virus is surging and overwhelming them? Or are they worsening, instead, because their immune system has accelerated into a harmful hyperimmune phase that is making them severely ill, despite clearance of the virus (or substantial reduction of the viral load)? Or, are both problems occurring? If both problems are occurring, which is the more threatening problem? In such a circumstance it would be helpful to know whether the patient’s PCR test was still positive, and if so, at what Ct value. As discussed below, in such a circumstance it is important to realize that the result of a PCR test on a nasal swab may or may not be the same as the result of a PCR test done on a swab from the lower respiratory tract (LRT).

COVID-19 PCR test results on a swab from the lower respiratory tract (LRT) versus a swab from the nasal passages:

The result of a PCR test on a nasal swab may or may not be the same as the result of a PCR test performed, simultaneously, on a swab (if clinically indicated) from the lower respiratory tract (obtained, e.g., upon bronchoscopy or when a patient is intubated). For example, conceivably, a patient in the hospital could have a strongly positive PCR test on a nasal swab (due to a high viral load in their nasal passages) but a negative PCR test (if clinically indicated and performed) on a simultaneously obtained swab of their bronchial mucosa (because their immune system was able to prevent or control infection of their LRT). Another patient, one in the ICU, might have equally positive PCR test results in the nasal passages and the LRT, due to equally severe infection in both locations. It is also conceivable that a patient in the ICU could have a negative (or minimally positive) PCR test in their nasal passages (because their immune system was able to clear the virus in that location) but a strongly positive PCR test in the LRT (because of great difficulty clearing severe infection of the LRT). Therefore, in a hospitalized patient, it is presumptuous to assume that the result of a PCR test on a swab of the bronchial mucosa (if clinically indicated) would be the same as a simultaneously obtained swab of the nasal mucosa.

If a patient has a negative (or minimally positive) PCR result on a nasal swab and does not have evidence of LRT disease (no LRT symptoms or radiographic evidence of pneumonia), then it is reasonable to assume that a PCR test on bronchial mucosa (if it were to be done) would also be negative or minimally positive, and, therefore, would not need to be done. If a hospitalized patient with COVID-19 has a negative or minimally positive PCR test on a nasal swab performed on day 8, for example, of their illness (or earlier) but has evidence of considerable LRT disease, it is important to ask: Is the LRT disease due to active viral infection in the LRT; or is it due to a great amount of inflammatory immune reaction in the LRT without significant accompanying ongoing active viral infection; or is it due to a combination of active viral infection and an intense inflammatory immune reaction (and if so, which component is most threatening). To answer this question, it would be helpful to perform a COVID PCR test on a swab from the bronchial mucosa and, if positive, to note the Ct value at which it was positive. In addition, tests can be done to gauge the extent of inflammation/cytokine storm. If the PCR test on bronchial mucosa is negative, and tests for cytokine storm are positive, this would suggest that the considerable inflammation in the LRT is not due to active viral infection in the LRT but, rather, to an intense inflammatory immune reaction that has successfully cleared the virus but has left the LRT severely inflamed—in which case immunosuppression might be indicated.

Why have Ct values not routinely been included in the official lab reports of positive COVID-19 PCR tests?

It is unclear why Ct values have not routinely been included in the official lab reports of all positive COVID-19 PCR tests. In many hospitals and clinics patients and their physicians have not routinely been informed of the Ct values of “positive” tests. Many physicians have never heard of the Ct value and, therefore, do not even know to ask for it.

One explanation for the policy of not disclosing Ct values has been the claim that “including the Ct value in the PCR report would create too much confusion. It would take too much time for lab personnel to explain a reported Ct value to an inquiring physician, and it would take too much time for physicians to explain Ct results to their patients. Besides, there is considerable variability in Ct results, depending on the manufacturer of the PCR test and on the correctness and uniformity of lab technique. When a swab from the same person is tested with two different test kits, or in two different labs, the two Ct values might differ. This could lead to confusion and false conclusions. It would open up a huge can of worms to disclose Ct values.”

There is some truth to the above claims. However, despite the above complexities and limitations, patients and their physicians deserve to know and need to know the Ct value of any positive test. Whatever amount of time and effort is needed to educate physicians and patients about a Ct result should be spent. And laboratory regulatory bodies can and should ensure that there is better uniformity of Ct results among different manufacturers and in different labs. There is no legitimate scientific, clinical, or ethical excuse for not disclosing the Ct value of all positive tests and for not thoroughly educating physicians, patients, and the general public about Ct values.

Regarding home antigen testing for COVID-19:

In anticipation of a highly virulent variant, it will be important for outpatients with COVID-19 to do home COVID-19 antigen tests early (within 1-2 days after onset of symptoms) and serially (every 1-3 days, as needed).

The home antigen tests provide a “positive” or “negative” result, regarding presence or absence of SARS-CoV-2 antigen (nucleocapsid) in the nasal mucosa. Although the home antigen tests were not specifically designed to indicate the quantity of virus present (viral load) and have not been formally tested to determine whether they can be used to estimate viral load, I would like to share observations that suggest that serial home antigen testing might provide some helpful information regarding initial and subsequent viral load.

At the very beginning of COVID-19 illness (during the first 24 hours after onset of symptoms) it is possible that the home antigen test might, in some cases, be negative. That is, after about a minute, the “Control” bar becomes brightly positive, but the “Test” bar remains unequivocally negative throughout the entire 15 minutes of the test.

At some point within the first two days of illness, the home antigen test is apt to become positive. In some such instances, the test quickly becomes very strongly positive—e.g., the “Test” bar might become very bright even before the “Control” bar becomes similarly bright. In other instances, the “Control” bar becomes very bright (as usual) at the usual one minute mark (or so) and the “Test” bar becomes only faintly positive at about the same time (even later) and becomes only a little brighter during the remaining minutes of the test. A spectrum of possibilities is possible between these two extremes.

It is tempting to think that in the first instance the rapid onset of a brightly positive “Test” bar (even before the “Control” bar becomes positive) means that a very high viral load is present; and that in the second instance the delayed appearance of only a faintly bright “Test” bar means that the person has only a low load of virus. This is assuming that in both instances the nasal swabbing and use of the test kit were done correctly and equally correctly. Although it is tempting to conclude such, it is wise to not draw that conclusion with any certainty. But, with each testing, it is worth noting and recording how strongly positive the “Test” bar became and how soon it reached its maximum brightness (positivity).

If an individual person’s initial test (during the first 1-2 days after onset of symptoms) was strongly positive (e.g., the “Test” bar became very strongly positive even before the “Control” bar turned positive) and then, upon serial testing (repeat testing every 1-3 days), the “Test” bar became positive increasingly less quickly and increasingly less brightly and eventually became negative (on day 8-10, e.g.), it is tempting to think that those particular serial test results indicate that the person’s viral load was substantially, steadily, and increasingly diminishing and that little or no virus was still present by day 8-10. Again, although it is tempting to conclude such, it is wise to not draw that conclusion with any certainty. But it is worth noting, recording, and comparing how strongly positive the “Test” bar became and how soon it reached its maximum brightness (positivity) on each of the serial tests.

Again, the COVID-19 home antigen tests were not designed for quantitation of viral load, nor have they been tested to determine whether they can be reliably used in the above fashion to grossly estimate (and serially follow) viral load. But, paying attention to such details, initially and serially, seems better than ignoring such details, as long as the limitations of doing so are kept in mind.

It is unclear why formal studies have not been done to determine the extent to which serial home antigen tests can be reliably used in the above-described fashion to serially estimate viral load. Common sense suggests that it would have been important and helpful to have conducted such a study, long ago.

Closing Comment:

At the very least, it is hoped that this article will stimulate and facilitate respectful scientific dialogue among physicians, nurses, other health care workers, public health officials, and the general public regarding how to best prepare for the potential arrival of a highly virulent SARS-CoV-2 variant.

RELATED READINGS:

For additional thoughts and suggestions regarding how to prepare for and meet the challenge of a highly virulent variant, please see the original article, In Anticipation of a Highly Virulent SARS-CoV-2 Variant: https://notesfromthesocialclinic.org/in-anticipation-of-a-highly-virulent-sars-cov-2-variant/

Also, please see: How Has the COVID-19 Mass Vaccination Campaign Made the Natural Selection and Rapid Propagation of a Highly Virulent Variant Highly Likely? https://www.trialsitenews.com/a/how-has-the-covid-19-mass-vaccination-campaign-made-the-natural-selection-and-rapid-propagation-of-a-highly-virulent-variant-highly-likely-44952cc7

For additional information, see the many articles that are posted in the “Notes on COVID-19” section of the following website: www.notesfromthesocialclinic.org

In particular, please see the following articles:

Respecting the Immune Ecosystem: https://notesfromthesocialclinic.org/respecting-the-immune-ecosystem-slide-by-slide-written-transcript/

Treatment of Severe COVID-19: https://notesfromthesocialclinic.org/treatment-of-severe-covid-19-illness-long-version/

The Importance of Knowing the Ct Value at which a COVID PCR Test is Positive: https://notesfromthesocialclinic.org/the-importance-of-knowing-the-ct-value-at-which-covid-pcr-tests-are-positive-long-version/

How Would Three of Canada’s Greatest Historical Figures Respond to the COVID Situation If They Were Alive Today? https://notesfromthesocialclinic.org/how-would-three-of-canadas-greatest-historical-figures-respond-to-the-covid-situation-if-they-were-alive-today

An Open Letter to Parents and Pediatricians https://notesfromthesocialclinic.org/an-open-letter-to-parents-and-pediatricians-2/

Also, please see articles posted on Dr. Geert Vanden Bossche’s website: www.voiceforscienceandsolidarity.org

And, read Dr. Vanden Bossche’s recent book, The inescapable Immune Escape Pandemic.