What Your Doctor May Consider if COVID-19 Symptoms Worsen 

     

The name of the virus that causes COVID-19 disease is SARS/CoV-2.

 

SARS/CoV-2 stands for:

 

Severe Acute Respiratory Syndrome/Corona Virus-2

 

This name refers to the clinical syndrome that may occur with this novel coronavirus to include severe damage to the lungs.

 

Most patients at the time of this writing appear to incur so-called “mild” or “moderate” COVID-19 disease which includes asymptomatic individuals. 

 

COVID-19 patients that worsen to “severe” or “critical” stages are sometimes encountering multi-system organ damage.

 

This damage occurs in the brain, heart, kidneys, lungs and other organs. It is being recognized as a consequence of prolonged hospital stays, especially those who require significant time on a mechanical ventilator.

 

An intriguing and important unanswered question at the time of this writing is whether the multi-system damage some patients suffer is due to one or all the following:

 

  1. Direct injury inflicted by the SARS/CoV-2 virus

  2. Pro-inflammatory cytokines (Cytokine Storm Syndrome)

  3. Hypercoagulation of blood in blood vessels and lungs

  4. Prolonged hospitalization, especially those on ventilator support

 

Our objective is to convey findings that may reduce the progression of COVID-19 to “severe” or “critical” stages that cause patients to require mechanical ventilator life support.

Too many COVID-19 patients placed on mechanical ventilators are not surviving.

 

Misinformation About Ventilator Efficacy

 

The government, media, and most medical professions have touted the need for more respiratory ventilators to spare the lives of COVID-19 patients.

 

As it relates to COVID-19, however, emerging data suggest that 65% or more of patients requiring long term invasive mechanical ventilation in the ICU die from pneumonia, sepsis, and/or multi-organ failure.[1]

 

While the shortage of ventilators has been a major talking point, the reality is that invasive mechanical ventilation is far less a solution and more a temporary measure that prolongs life rather than providing curative treatment for most patients.  

 

Avoiding ICU invasive mechanical ventilation and worsening clinical status are critical for any patient with progression to severe COVID-19 disease.  

Need for Early Interventions

 

The medical advice at the time of this writing from the CDC and World Health Organization (WHO) is to ask patients with “mild” COVID-19 symptoms to isolate themselves at home, use over-the-counter medications like acetaminophen to reduce fever, and report any worsening symptoms, especially  difficulty breathing. 

 

If clinical symptoms worsen, the symptomatic patient is often rushed to a crowded hospital ER and assessed.

 

There is no consistent data at the time of this writing to effectively gauge surrogate blood markers that may place a COVID-19 patient at greater risk of deteriorating into a “severe or critical” stages of the disease where invasive ventilator support is required.

 

Findings from some recent studies suggest more can potentially be done to identify the subgroup of people with worsening COVID-19 disease, and those patients at risk for progressing to advanced stages.

 

These studies provide an experimental rationale for using existing drugs to suppress interleukin-6 and other pro-inflammatory factors responsible for the cytokine release syndrome.

 

Often called the “cytokine storm”, this hyper-inflammatory state may be a significant cause of tissue damage and death from severe COVID-19 disease.  

 

Today’s Treatment Dilemma

 

Heroic physicians, nurses, respiratory technicians, and other healthcare workers are on the front lines in “hot zone” COVID-19 regions of the country.

 

These medical staffs are overwhelmed by a lack of personal protective equipment as well as a lack of well-validated treatment options to prevent progression of COVID-19 to severe disease requiring invasive mechanical ventilation.

 

At the time of this writing, there has been a large volume of hastily published medical literature on COVID-19 and frequent pre-prints of observational data that has not been peer-reviewed. This has collectively created confusion about the “best” available option for desperate patients and medical professionals struggling to treat them effectively.

 

Symptomatic people today often wait weeks to either slowly recover or worsen to the point of needing hospitalization.

Once in the hospital, many COVID-19 patients deteriorate and require ICU/ventilator support with most not surviving at the time of this writing. 

There is no consistent medical protocol as to what COVID-19-symptomatic persons can and should do during infection, especially those unfortunate patients that evolve to severe stages of COVID-19/ SARS-CoV-2.  

Some recent studies hint at potential benefits if blood levels of pro-inflammatory cytokines are measured in COVID-19 patients to identify those at risk of progressing to severe disease.

 

The authors of some of these studies suggest IL-6 blocking drugs be carefully used to suppress the cytokine release syndrome that can manifest in severe disease.

A Report of Inflammatory Blood

Markers in COVID-19 Patients

 

A prepublication released on April 1, 2020 reported on a small number of COVID-19 patients whose inflammatory blood markers were measured.[2]

 

The paper opens by describing how the substantial number of COVID-19 patients with severe disease have strained intensive care capacities to an unprecedented level.

 

The study authors point out the highly variable course of COVID-19 and lack of reliable predictors for patient deterioration.

 

The objective of their pilot study was to identify variables that allow physicians to predict which patients are at a high risk of respiratory failure and need of mechanical ventilation.

 

The study evaluated baseline clinical and laboratory findings of 40 patients with PCR-proven symptomatic COVID-19 infection hospitalized from February 29 to March 27, 2020.  

 

The study doctors found that elevated blood levels of the pro-inflammatory cytokine interleukin-6 (IL-6) was strongly associated with the need for mechanical ventilation.

 

In this small study group, patients with IL-6 blood levels over 80 pg/ml were at 22 times higher risk of respiratory failure compared to patients with lower IL-6 levels.

 

The doctors also noted high baseline levels of C-reactive protein (CRP), troponin T (a marker of cardiac damage) and other markers of infectious inflammation in these newly hospitalized COVID-19 patients.

 

This finding suggests newly hospitalized COVID-19 patients are already in a pro-inflammatory state with possible organ damage.  

 

Another bit of data from this pilot study was that once IL-6 elevates over 80 pg/mL, respiratory failure developed on average of only 1.5 days (range of 0-4 days). This indicates a need for rapid decision making as it relates to consideration of drugs that block IL-6.

 

The study concluded with the doctors stating:

 

“Our study shows that IL-6 is an effective marker that might be able to predict upcoming            respiratory failure with high accuracy and help physicians correctly allocate patients at   an early stage.”

To put this 80 pg/mL of IL-6 into context, Life Extension® added IL-6 to a special Age Management Blood Test Panel in 2019-2020. Test results of 474 blood samples had a median result for IL-6 of only 1.7 pg/mL. The highest reading was 24.7 pg/mL with a handful over 10 pg/mL.

From what we’ve been able to review, COVID-19 patients who progress to the point of needing to go to the hospital are already in a significant pro-inflammatory condition.

A critical question is whether this inflammation is needed to fight the virus or is the inflammation an over-reaction by the immune system that is inflicting needless damage to healthy tissues.

And to throw in one more variable, different laboratories often use different testing methods which often produce different numbers. This is a huge problem when trying to compare numbers from multiple studies.

Researchers struggle with this issue, especially when pooling data from several studies, which is what I am attempting to do here as it relates to elevated IL-6 (and other cytokines) and their association with worsening COVID-19 disease.

Recent Clinical Observations May Reveal a Game Plan

Preliminary clinical (human) research reports offer intriguing support that may lay the groundwork for symptomatic COVID-19 patients to utilize pro-inflammatory cytokine blood tests as a means of identifying their risk of progression to severe disease.

If pro-inflammatory biomarkers are elevated, consideration can then be made by the treating physician to prescribe IL-6 blocking drugs like tocilizumab (Actemra®).  

In the first of these studies I report on, COVID-19 disease severity was found to be statistically significantly associated with age and specific blood markers

The authors of this study advocate for considering the use of IL-6 suppressing drug therapy in COVID-19 patients with elevated pro-inflammatory blood levels.

An extensive array of immune functions and pro-inflammatory factors were measured in this study that when elevated can create a deadly “cytokine storm”.

Below is the list of blood tests used to in this study to identify the inflammatory status of COVID-19 patients:

  • Interleukin-2 receptor (IL2R)

  • Iinterleukin-6 (IL-6)

  • Interleukin-8 (IL-8)

  • Interleukin-10 (IL-10)

  • Tumor necrosis factor α (TNFα)

  • C-reactive protein (CRP)

  • Ferroprotein

  • Procalcitonin

  • White cell counts (WBC)

  • Lymphocyte counts

  • Neutrophil count 

  • Eosinophil counts

 

The authors of this study concluded:

“Inflammation is closely related to severity of COVID-19, and IL-6, TNFα and IL-8 might be promising therapeutic targets.”

The name of this study that measured this broad spectrum of immune and inflammatory blood markers is:

 

“Correlation Analysis Between Disease Severity and Inflammation-

 related Parameters in Patients with COVID-19 Pneumonia”3

 

This study emphasized the role that inflammation has on disease progression based on previously published research.

The authors of this study then analyzed blood inflammation indicators among mild, severe, and critical COVID-19 patients to “identify severe or critical patients early”.

This study consisted of 100 COVID-19 patients, 34 patients in the mild group, 34 were severe, and 32 were critical stage.

As it related to interleukin-2 receptor (IL2R) blood levels, there were significant differences amongst these COVID-19 patients as follows:

    Patient Group                                  IL2R Inflammatory Marker

Mild                                                      486.44 U/mL

Severe                                                 885.09 U/mL

Critical                                               1317.31 U/mL

Interleukin-2 is usually viewed as a beneficial immune cytokine because it activates natural killer (NK) cells.

NK cells are the body’s first line of defense against viral (and other) infections.

A plausible problem with some COVID-19 patients developing severe disease appears to be over-activation of a host of immune/inflammatory factors as the disease worsens.

Some interpret this data as indicating that activating IL-2 and other acute phase immune responses such as Type 1 interferons before one is fully infected with the COVID-19 virus may prevent infection from taking hold.

Once more advanced or severe COVID-19 infection sets in, however, the IL-2 receptor (and other immune components) can become over-activated and cause the deadly “cytokine storm”.

As you will read next, the primary “cytokine storm” culprit appears to be interleukin-6 (IL-6).

                                 

Potential Deadly Role of Elevated

IL-6 in Severe COVID-19 Disease

The authors found that “mild” COVID-19 patients had IL-6 blood levels under 100 pg/mL and those with more advanced illness were significantly higher.

Recall the initial study I reported on in this editorial found that hospitalized patients with IL-6 blood levels over 80 pg/mL were 22 times more likely to progress to respiratory failure.

 

Update: One of our advisors suggested that ICU/ER physicians consider an IL-6 blood level over 50 pg/mL as a tentative indicator for IL-6 antagonist therapy with Actemra® or other cytokine suppressing drugs to be initiated.  

As people age, a pathological process of immune senescence sets in that is partially characterized by over-activation of interleukin-6 (IL-6) signaling.4,5,6

This manifests in older people as a chronic inflammatory state that underlies common diseases of aging. People who live to age 100 typically express low levels of IL-6. 7

Anti-aging advocacy groups have sought for many years to target excess IL-6 to delay the onset of degenerative aging.

As it relates to COVID-19, a sharp spike in IL-6 signaling may be a primary causative factor behind the deadly “cytokine storm”.

The study I am relaying here found that IL-6 blood levels were significantly different among mild, severe, and critical Covid-19 groups.

The authors found that “mild” COVID-19 patients had IL-6 blood levels under 100 pg/mL and those with more advanced illness were significantly higher.

Recall the initial study I reported on in this editorial found that hospitalized patients with IL-6 blood levels over 80 pg/mL were 22 times more likely to progress to respiratory failure.

Assuming the testing methodologies are roughly equivalent (and this is an assumption at this point), these studies appear to corroborate each other as it relates to higher IL-6 being associated with worsening COVID-19 disease.

Rationale to Test IL-6 Blood Levels if Symptomatic

Some of our supporters have their IL-6 blood levels checked because they understand the toxic impact that elevated IL-6 inflicts during normal aging.  

Based on recent findings, a person with “mild” COVID-19 symptoms might want to have an IL-6 blood test to ascertain their baseline in the “mild” phase of the disease. This can help evaluate their risk of worsening to advanced stages. It also provides knowledge of one’s baseline IL-6 to compare it to future tests that may show IL-6 spiking higher in response to COVID-19 progression.

Obese individuals are likely to have higher IL-6. When infected with the COVID-19 virus, IL-6 may skyrocket to lethal levels in those with underlying inflammatory disorders.

This might partially explain why obese and type II diabetics succumb to COVID-19 more frequently as their pro-inflammatory levels are high to begin with.

Knowing one’s IL-6 history provides a clue to the physician to determine if an IL-6 signaling blocker drug called tocilizumab (Actemra®) should be prescribed.

Current thinking amongst some physicians is to target elevated IL-6 with tocilizumab (Actemra®).

A concern might be raised about over-suppression of certain immune functions needed for fight off the SARS/CoV2 virus. Therefore, use of these cytokine-suppressing drugs should be viewed as experimental.

As it relates to other inflammatory markers, blood levels of C-reactive protein, TNF-a and procalcitonin were elevated based on mild, severe and critical COVID-19 status in the study I am describing.

                         

Immune Cell Count levels in COVID-19 Patients

The response to infectious disease severity can often be seen by elevated immune cell counts.

In the study I continue to describe, a white blood cell called a neutrophil was found to be elevated as COVID-19 status worsened as follows:

     Patient Status                                          Neutrophil Count

 

   Mild                                                           3.53

 

   Severe                                                       5.47

  Critical                                                      10.80

There were significant differences in total white blood cell counts, lymphocyte counts, and other immune markers that may provide surrogate measures of underlying disease status.

This can be of immense value to a treating physician and an empowered patient who pays attention to their blood test results.

Discussion of this Study’s Findings

As dozens of experimental therapies are being tested on thousands of COVID-19 patients, having the prognostic ability of surrogate blood markers is of considerable potential value.

These readily available blood tests may better identify critical COVID-19 patients and help with clinical decision-making.

The study I am reporting on corroborates previously published research showing increased IL-6 and other inflammatory factors to be associated with the severity of COVID-19 pneumonia.

 

TNFα, neutrophil and lymphocyte counts were correlated with disease severity, which is analogous to findings from another published study.  Additional inflammatory indicators were also related to the disease severity.

 

IL-6 levels in mild patients were lower than 100 pg/mL.

 

When IL-6 exceeded 100 pg/mL, the study authors postulate this might represent the emergence of an “inflammatory storm”.  (This is also referred to as “cytokine release syndrome” or “cytokine storm”.)

 

The following blood markers were found to indicate progression to critical COVID-19 illness:

                

                            Blood Marker                       Danger Zone

                      White Blood Cell count              Over 9.5

                      Neutrophil count                        Over 7.30  

                      C-reactive protein (CRP)            Over 30.7ng/mL

                      Interleukin-2 receptor                 Over 793.5U/mL,     

               

                      Ferroprotein                                Over 2252 ug/L

Testing as many of these inflammatory markers as is feasible may play a role in identifying the potential for progression from “mild” to “severe” and “critical” disease earlier in COVID-19/ SARS-CoV-2 infection.  

This provides an earlier opportunity to suppress elevated IL-6 and possibly other pro-inflammatory cytokines to potentially improve the recovery rate and reduce organ damage and mortality in patients who evolve to severe COVID-19 disease.

What we don’t know is what impact prematurely suppressing IL-6 and other pro-inflammatory cytokines will have on the patient’s ability to bring the viral infection under control. I suspect it will require a delicate balance with highly experienced ICU physicians. More guidance on this is provided later in this article.

 

Interleukin-6 Blocking Drug Therapy

The next study I describe is titled:

“Can we use interleukin-6 (IL-6) blockade for coronavirus disease 2019 (COVID-19)-induced cytokine release syndrome (CRS)?”8

The conclusion of the study authors is:

“We propose to utilize interleukin-6 (IL-6) blockade to manage COVID-19-induced CRS (cytokine release syndrome) and discuss several factors that should be taken into consideration for its clinical application.”

So far I’ve reported on findings showing that IL-6 blood levels over 80 pg/mL can enable emergency room and ICU physicians to predict which COVID-19 patients will worsen and require ventilator support.

 

The purpose of this study was not to consider using an IL-6 suppressing drug, but to better manage patients in crowded emergency rooms and intensive care units (ICU).

 

I next reviewed an elaborate study that identified elevated pro-inflammatory cytokines in COVID-19 patients and suggested that IL-6 drug suppressing therapies be considered as a method to reduce morbidity and mortality.

 

In the study I report on now, the authors make a stronger case for considering IL-6 blockade in the treatment of COVID-19 disease.9

 

The authors of this study observed that people suffer COVID-19 symptoms 9.5 to 12 days before requiring intensive (ICU) care.

 

The authors further state that in addition to acute respiratory distress (pneumonia) necessitating ventilator support (67% of patients), multi-day progression leads to acute kidney injury (29%), acute cardiac injury (23%), and liver dysfunction (29%).

 

This delay from onset of initial symptoms to severe or critical COVID-19 disease, the study authors submit, provides a window to test symptomatic patients for increased proinflammatory cytokines and perhaps initiate anti-cytokine treatment if blood markers and patient symptomology indicates likelihood of disease progression.

 

The authors of the study I am describing report death rates of critically ill patients as high as 49.0–61.5% and cite evidence suggesting that the “cytokine storm” might play a major role in severe COVID-19.

 

They note that a host of inflammatory factors including interleukin-6 are significantly elevated in COVID-19 patients, and some are more commonly seen in severe patients than in non-severe patients.

 

The authors go on to relate autopsy findings in COVID-19 patients with elevated inflammatory cytokines that reveal tissue death and abnormal immune cell infiltrations in the lung, heart and gastrointestinal mucosa. These findings suggest dysregulated immune responses.

Cytokine Storms not unique to COVID-19

 

Some in the media are now discussing the proinflammatory “cytokine storm”, but this is not a new phenomenon.

 

Cytokine storms relate to over-active immune systems. They are causative or contributing underlying pathologies in those who contract sepsis, suffer the effects of immune-based cancer drugs, develop graft-versus-host disease, and rheumatoid disorders.10,11,12,12,14,15

 

It is because of “cytokine storm” related disorders that FDA-approved drugs are available now like tocilizumab (Actemra®) that impede IL-6 signaling, which is a major pro-inflammatory cytokine.

 Balancing Immune Responses  

 

Previous studies have shown that severe respiratory distress (pneumonia) occurs in some patients infected with coronaviruses despite a diminishing viral load.

 

This implies that antiviral therapy alone may be inadequate to protect tissues throughout the body from acute and permanent inflammatory damage.  This includes the heart, liver, brain and kidneys, where reports of COVID-19 patients requiring kidney dialysis are manifesting in hospital ICUs.16,17

 

Corticosteroid anti-inflammatory agents were initially widely prescribed in treating COVID-19 patients in the ICU setting. The problem with steroid drugs like prednisone is that they systemically shut down critical immune functions, as opposed to targeting one cytokine like IL-6 that is a major factor involved in the cytokine storm.

 

Other therapies aiming to dampen excessive serum inflammatory mediators are being developed, but COVID-19 patients may benefit now from drugs like Actemra® that target IL-6 signaling.

 

The authors of the study I am reporting on propose that reducing the detrimental over-active immune response with targeted drugs that block cytokines like IL-6 may be a beneficial addition to antiviral therapy.

 

Please know that at the time of this writing, it is not clear whether the SARS/Cov2 virus itself or the pro-inflammatory cytokine storm is the major causative factor in multi-organ damage. It might be a combination of the two, which is why effective antiviral therapy is urgently needed.

 

Sidebar--------

 

Fighting off Viruses Before Severe Disease Manifests  

 

In theory, if one could detect initial infection with the SARS/Cov2 virus and mount an immediate type 1 interferon response, then the virus could be eradicated by activated natural killer cells before serious COVID-19 disease manifested.

 

The delayed interferon response can be a factor that enables viruses to infect many cells and replicate out of control before the body’s adaptive immune system can mount an effective response.

 

This dampened type I interferon response in nasal, airway and alveolar lung cells can result in rapid coronavirus viral replication.

Said differently, coronaviruses can initially evade pathogen immune recognition, which enables viruses to gain a foothold in the body before an effective immune response can be mounted.  

 

Once systemic viral infection sets in, then excessive production of interferons may contribute to the “cytokine storm” while simultaneously turning down critical antiviral responses (such as inducing premature apoptosis of T-cells and depleting vital lymphocytes).

 

That’s why tamping down the excessive inflammatory responses by targeting specific factors like IL-6 may be so important once COVID-19 progresses.

A study published on May 15, 2020, however, indicated that administration of the interferon-alpha drug in nebulized form (inhaled into the lungs) along with an anti-viral drug called (arbidol) reduced the duration of detectable SARS/Cov-2 (virus) in the upper respiratory tract with a concomitant reduction in IL-6 and C-reactive protein inflammatory markers.  

The full text to this is open label study of 77 hospitalized patients in Wuhan can be reviewed at:

                        https://www.frontiersin.org/articles/10.3389/fimmu.2020.01061/full

A study published in The Lancet on May 8 2020 found a triple drug combination of interferon-alpha, ribavirin, and lopinavir-rotonavir was more in alleviating symptoms and shortening the duration of viral shedding and hospital stay in patients with mild to moderate COVID-19 than lopinavir-rotonavir alone. Here is link to full text article:

          https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31042-4/fulltext

The New England Journal of Medicine picked up on this research and wrote the following summary on May 16 2020:

"A combination of three antivirals — Kaletra (which is lopinavir plus ritonavir) and ribavirin — when given early and with interferon significantly reduces viral shedding, disease symptoms, and hospital stay in  patients with COVID-19 when compared with a control regimen of Kaletra alone. The drugs are active against other coronaviruses, but the key factors seem to be interferon and promptness of treatment.

When the triple-drug combo was administered without interferon 7 days or more after the onset of symptoms, the results were no better than with Kaletra alone. Prof. Ivan Hung, the lead author on the report, explains that the researchers were afraid of prompting a cytokine “storm” if interferon was given after 6 days of symptoms — they’re not sure that that reluctance was well founded now. In any case, no patients died in either group.

The study was conducted in Hong Kong and has just been published in The Lancet. (An earlier study by another group published in the New England Journal of Medicine found no special benefit from Kaletra alone — a result seemingly confirmed by this study in The Lancet.)

We were able to interview Prof. Hung over ZOOM from Hong Kong, where he was about to enjoy a Mother’s Day lunch with his mom. It was very generous of him.

Here is a link to the podcast:

https://podcasts.jwatch.org/index.php/podcast-266-interferon-and-early-treatment-in-covid-19-bring-good-outcomes/2020/05/10/?query=C19

 

End sidebar-------------

 

Preventing Systemic Cytokine Storms

 

In the lungs of many COVID-19 patients, there is a raging battle as the immune system seeks to eradicate the viral infection. This results in overwhelming “collateral damage” to lung tissues.

 

While the immediate clinical concern is protecting against pneumonia, the proinflammatory cytokines and COVID-19 viruses may also leak from the lungs into systemic circulation, leading to complications like dysregulated coagulation and multi-organ failure.

 

All this points to the critical need of identifying effective antiviral therapies and suppressing over-production of pro-inflammatory cytokines like IL-6.

 

Deadly role of IL-6 in Normal Aged Persons

 

Long after COVID-19 infections are brought under control, elevated interleukin-6 levels can inflict systemic inflammatory damage in the elderly, along with obese individuals, type II diabetics, and those inflicted with rheumatoid disorders.

 

Among the excessive pro-inflammatory factors produced in the body, IL-6 is one of the key cytokines.

 

Elevated IL-6 levels have been observed in corona patients and correlate with disease severity.

 

Excessive IL-6 signaling leads to a myriad of pathologic effects that contribute to organ damage and reduction of beneficial immune functions.

 

As the authors of the study I am reporting on note, elevated cytokine levels may be responsible for the lethal complications of COVID-19.

 

While the immediate focus is saving COVID-19 victims from IL-6 induced cytokine storms, long term strategies to suppress inflammatory factors (like elevated IL-6) should be implemented by those seeking healthy longevity.

 

Focusing on IL-6 Suppression

 

There are several potential inflammatory cytokine blockade therapies that may be effective for COVID-19.

 

The authors of the study I am reporting on believe IL-6 blockade may be the most promising strategy to combat the COVID-19 induced “cytokine storm”.

 

They note that elevated IL-6 levels were consistently reported in several studies of COVID-19 and might serve as a predictive biomarker for disease severity.8

 

The researchers reference a large retrospective cohort study showing that IL-6 levels were correlated with mortality in COVID-19 patients.

 

Based on a preponderance of published data, the authors state that:

 

“targeting IL-6 may be effective for COVID-19-induced cytokine release syndrome.”

 

Clinical use of an IL-6 signaling blocking drug

 

Actemra® (tocilizumab) is an anti-IL‐6 receptor drug.

 

It binds to IL-6 receptors to inhibit IL‐6‐induced inflammatory signaling.

 

Actemra® is approved by the FDA for the treatment of severe cancer treatment induced “cytokine storms”/cytokine release syndrome in cancer patients. 

 

IL-6 is a central intermediary of toxicity in cytokine release syndromes, meaning that suppressing IL-6 can offset the adverse impact of other inflammatory factors such as elevated TNF-a and interferons.

 

Actemra® has shown promising efficacy in severe “cytokine storm” syndromes.

 

A group of cancer patients suffering from “cytokine storm” side effects from immunotherapy were evaluated. After one or two Actemra® doses, 69% of patients responded within 14 days. Fever and hypotension resolved within hours, and life supporting drugs could be weaned in several days.18

 

The effect of Actemra® has also been reported in suppressing “cytokine storms” related to other conditions including sepsis.19

 

As the authors of the study I am reporting on state, Actemra® has significant safety data with the most common serious adverse effect being infections in patients with rheumatoid arthritis, in which chronic Actemra® therapy was maintained.  (Prophylactic antibiotics therapy can mitigate this risk.)

 

Other known side effects of Actemra® include hypertension, liver impairment and mucosal/skin rashes. These are manageable conditions and largely pale in comparison to the systemic damage inflicted by a chronic “cytokine storm”.

 

Repurposing Actemra® to treat COVID-19

 

Based on the efficacy of Actemra® in suppressing the cytokine storm in other disease conditions, the authors of the study I am reporting on propose to “repurpose Actemra® to treat severe cases of COVID-19.”

 

They also propose early diagnosis of a developing cytokine storm in COVID-19 patients and prompt initiation of IL-6 suppressing therapy if warranted.

 

The open question is exactly when anti-IL-6 drug therapy should be initiated.

 

As it relates to cancer treatment using immune boosting CAR-T cell therapy, prematurely turning down the cytokine storm can negate the anti-cancer immune benefits. This can translate into treatment failure as not enough cancer cells are killed by the immune boosting CAR-T therapy.

 

The authors of the study I am reporting on state that this principle is not shared in viral infections such as COVID-19, in which “timely intervention in mild or moderate patients may prevent progression.” (This remains controversial at the time of this writing and it is not known if premature shutdown of IL-6 immune signaling may enable COVID-19 to worsen.)

 

The authors of this study note immune suppressing corticosteroid drugs may delay viral clearance but suggest that combining targeted IL-6 suppressing drug therapy with antiviral agents may add further benefit.

 

The study authors acknowledge uncertainties as to when anti-IL-6 drugs like Actemra® should be administered to COVID-19 patients.

 

They suggest close monitoring of blood levels of IL-6, C-reactive protein and other markers to ascertain patient’s inflammatory status and risk of progressing to advanced COVID-19 disease. They point to most studies find that elevated CRP levels are associated with severe COVID-19, with a few exceptions

 

They note the risk of secondary infections associated with immune modulators (like Actemra®) and suggest prophylactic antibiotic treatment may be indicated.

                                      Update from Cleveland Clinic Doctors

More recent clinical findings from the Cleveland Clinic help corroborate the potential  benefits of blocking excess interleukin-2 (using IL-6 receptor targeted drug therapy).

 

The Cleveland Clinic physicians noted that in the short term after an IL-6 blocking drug (like Actemra®) is administered, IL-6 blood levels increase because their target receptors are blocked by the drug.

So in monitoring the anti-inflammatory response to the IL-6 blocking drug, in lieu of testing blood levels for IL-6, these doctors recommend the following other blood markers of inflammation and coagulation risk:

                                                            1. C-reactive protein 

                                                            2. Ferritin

                                                            3. D-dimer

Emerging data indicates that hospitalized COVID-19 patients should have coagulation markers (like D-dimer) checked. If elevated, then the administration of low-molecular-weight heparin and possibly aspirin may prevent the vascular blood clotting (hyper-coagulation and thrombosis) that adversely impacts many advanced disease cases.

As you'll read towards the end of this article, some doctors are suggesting specific anti-coagulant and anti-thrombotic prophylaxis for appropriate hospitalized COVID-19 patients.

 

Reference: Cleveland Clinic website:

https://www.ccjm.org/content/early/2020/05/12/ccjm.87a.ccc018

Preliminary Report on IL-6 Blockade in Severe COVID-19

 

A clinical report released on April 20, 2020 provides further guidance as to when IL-6 blockade may be initiated in COVID-19 disease patients.20

The authors of this study acknowledge the data I’ve relayed so far that suggests physicians screen patients with severe COVID-19 for hyper-inflammation and investigate immunomodulatory drugs in this setting.

 

This authors then relay their “short-term, yet promising experience” regarding IL6 blockade with Actemra® in 30 COVID-19 pneumonia patients with the following criteria:

 

  • Less than 80 years of age

  • Over 5 days of prior disease duration

  • Severe (requiring over 6L/min of oxygen therapy)

  • Rapidly deteriorating (increase by more than 3L/min of oxygen flow within the previous 12 hours)

  • COVID-19-related pneumonia.

 

They compared these thirty COVID-19 pneumonia patients treated with the IL-6 blocking drug Actemra® with a control group of patients (matched for age, gender and disease severity) that did not receive Actemra®.

 

The authors demonstrate that in these highly selected COVID-19 patients, IL6 blockade could:

 

  • Curb the "cytokine storm"

  • Prevent ICU admission

  • Prevent the requirement for mechanical ventilation

 

While acknowledging the shortcomings of this retrospective small sample-size study, the authors conclude:

 

“…we believe that these preliminary findings support the fostering of research efforts in the fight against COVID-19-induced inflammation, especially before patients require admission to the ICU.”

 

 

Sidebar--------

Actemra® Dosing for COVID-19

 

At the time I was writing this review of recent studies, dozens of clinical trials are planned to study the effects of drugs like Actemra® to suppress the cytokine storm suffered by COVID-19 victims.

 

This makes it impossible to relate what the proper dosing protocol might be. With so many human lives being lost to COVID-19 each day, some educated conjecture is needed for those who want to go beyond “standard care”.

 

In treating severe or life-threatening cytokine release syndrome due to CAR-T immune cancer therapy, the dose of Actemra® (tocilizumab) is 8 mg per kilogram of body weight administered intravenously. It may be administered alone or in combination with corticosteroids.

 

If no clinical improvement in the signs and symptoms of cytokine release syndrome occurs after initial dose, Actemra® may be administered up to 3 additional doses but must allow 8-hour interval between consecutive doses.

 

For experimental use in COVID-19 patients, the core hypothesis in the planned and/or on-going experimental studies is that Actemra® may be effective in:

 

 “…decreasing signs, symptoms, and laboratory evidence of COVID-19 pneumonitis in hospitalized, non-critically ill patients with clinical risk factors for clinical decompensation, intensive care utilization, and death.”

 

Various dosing Actemra® regimens are being utilized in clinical practice and clinical trials. There is no established dose regimen in treating COVID-19 patients so there is no “best” dose regimen to recommend currently.

 

However, the most “common” experimental dosing regimen at the time of this writing with Actemra® (tocilizumab) seems to be 8 mg/kg intravenous (IV) up to a maximum of 800 mg with repetition of the same dosage after 12 hours if no clinical improvement (two doses total) is observed.

 

End sidebar-------------

 

 Problems with PCR Viral and SARS/Cov2 Antibody Tests

 

You might have noticed that we are not emphasizing at the time of this writing the need to test for the presence of the virus (SARS/CoV2) that causes COVID-19 or the antibodies (IgM and IgG) that indicate existing disease (IgM) or recovery from disease (IgG).

 

The reasons we view these as optional at the time of the writing of this editorial is that there are open questions as to accuracy of these tests, without well-documented evidence of consistent reliability and accuracy. This includes too many false negatives (with PCR tests).

 

A false negative on a PCR screening test means a person that has the virus that causes COVID-19 is told they don’t have the infection. 

 

PCR is a reliable technology, but in the context of COVID-19/ SARS-CoV-2 infection there remains a concern of inadequate collection specimens, with a subsequent increase in the rate of false negative test results, which may run as high as 30%

 

There remain accuracy concerns with antibody blood tests despite some of them being given emergency FDA approvals.

 

Since there are many strains of coronaviruses, there may be false positive IgG results, which imply a person has recovered from COVID-19 and thus immune from future infections.

 

The problem is it is too early to know if a positive IgG (SARS/Cov-2) test confers long term protection against relapse or if the person is still open to infection.

 

As we eagerly wait for fully validated testing methods, we advise treating the patient, and not treating a test result, especially in the context of PCR screening tests.  

 

Surrogate blood markers such as C-reactive protein, IL-6, immune cell counts, and other tests described in this article can help assess symptomatic patients at risk for progressing to severe or critical stage disease.

 

We are not suggesting that PCR or antibody tests be avoided by symptomatic individuals and their physicians. We are only questioning testing accuracy at this time.

                                                    Heparin's Multi-faceted Benefits

In reviewing Cleveland Clinic's helpful web series (https://www.ccjm.org/cc/covid-19-curbside-consults), the institution has provided an excellent coagulopathy algorithm that can be very helpful in management considerations of COVID-19 patients.

Coagulopathy is rapidly being recognized as a major problem with severe COVID-19, whereby small and large clots develop inside blood vessels causing a myriad of tissue and organ damage. These clots are appear in the lungs and interfere with breathing, and in arteries where they cause strokes, heart attacks and kidney impairments. 

Here is what the Cleveland Clinic initiailly disseminated on May 14 2020:

Heparin anti-coagulation seems to be the obvious response to such a hyper-coagulable process.

In addition to its anti-thrombotic effect, heparin may have anti-inflammatory, anti-complement, and direct antiviral effects that may be beneficial in COVID-19.

Heparin inhibits neutrophil activation, binds inflammatory cytokines, and reduces endothelial activation. 

Experimental models have also shown that heparin directly binds to SARS-CoV spike-protein1, which acts as the viral anchor site for SARS-CoV–ACE2 interaction, and thereby blocks cell entry.


While promising, these effects have yet to be demonstrated in clinical practice, and specific data on the management of CAC are extremely limited.

One study of 449 patients with severe COVID-19 showed no overall mortality difference (29.7% vs 30.3%, P = .910) between patients who did not and those who did receive heparin (94 patients on low-molecular-weight heparin, 5 patients on unfractionated heparin; prophylactic doses).

There was, however, a significant difference in mortality rates (32.8% vs 52.4%, P = .017) in the subgroup of patients with a D-dimer more than 6 times the upper limit of normal (> 3 μg/mL). The authors concluded that heparin improves mortality rates in patients with severe COVID-19 and cited a Chinese consensus statement as recommending anti-coagulation in severe COVID-19. It must be emphasized that this study retrospectively compared heparin prophylaxis vs no prophylaxis. It remains unclear if therapeutic anti-coagulation would provide additional benefit.

Thrombolysis in patients that deteriorate despite anti-coagulation has also been suggested. A small case series of patients with persistent severe hypoxia and markedly elevated D-dimer showed improvement in oxygenation after low-dose tissue plasminogen activator. Despite initial improvement and no reported adverse effects, the ultimate outcome in this series was poor.

Given this lack of evidence, the ASH (American Society of Hematology) and ISTH (International Society on Thrombosis and Haemostasis) currently do not recommend treatment above and beyond standard prophylaxis unless there is an established indication.

Both societies strongly recommend DVT prophylaxis in all patients on admission using low-molecular-weight heparin (unfractionated heparin in renal failure, fondaparinux in heparin-induced thrombocytopenia) and stress that prophylaxis should be continued even in the setting of thrombocytopenia (platelet count > 25 × 109/L). 

Reference link: https://www.ccjm.org/content/early/2020/05/12/ccjm.87a.ccc024

Staying informed…

 

The purpose of this website is to openly disseminate information that offers an opportunity to save lives, especially as it relates to re-purposing already approved drugs, along with reports of efficacy of newer medications.

 

These re-purposed drugs have known side effect risks that can assist prescribing physicians in estimating an experimental dose and when it might be most appropriate to initiate therapies such as Actemra®.

 

The purpose of this article is to disseminate research findings that provide preliminary data about potentially effective treatments for COVID-19 patients who deteriorate from mild/moderate disease to severe and critical stages requiring hospitalization.

 

This article was initiated in early April 2020 and mostly finalized around April 24, 2020. Tremendous efforts were made to ensure accuracy of the reporting of the experimental studies.

 

As new studies pour in, our group will attempt to post abstracts and links that can help keep you and your physician updated.

 

Direct links to many of the articles discussed in this review article can be accessed in the References section below.

 

To view additional abstracts and articles on these topics, click here or the Cytokine Storm button on bar at the top of this website.  

 

For longer life,

 

William Faloon, Volunteer

Age Reversal Network

 

 

WARNING!

 

Given the rapid and evolving nature of medical/scientific data on COVID-19/ SARS-CoV-2, some or most of the information in this article and/or website may be rendered obsolete, or worse, incorrect at any future time. 

Much more validated data is likely to be discovered over the next several months.

The reports contained herein are based largely on pre-publication reports and evidence from previous published studies.

If you contemplate initiating any of the suggestions discussed on this website, please remember that these are all still in experimental stages and not subject to rigorous clinical trial design, execution or peer review.

Data pertaining to experimental treatment options are disseminated for public education purposes.

COVID-19 patients and their families may choose to share this information with treating physicians for experimental considerations.

 

References:

[i] Coronavirus disease 2019 (COVID-19): Critical care issues. Available at:

https://www.uptodate.com/contents/coronavirus-disease-2019-covid-19-critical-care-issues.  Accessed May 1, 2020. 

[ii] Level of IL-6 predicts respiratory failure in hospitalized symptomatic COVID-19 patients. Available at:

https://www.medrxiv.org/content/10.1101/2020.04.01.20047381v2. Accessed May 1, 2020.

[iii] https://www.medrxiv.org/content/10.1101/2020.02.25.20025643v1. Accessed May 1, 2020.

[iv] IL-6-STAT3 signaling and premature senescence. Available at:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3876432/. Accessed May 1, 2020.

[v] Cellular senescence or EGFR signaling induces Interleukin 6 (IL-6) receptor expression controlled by mammalian target of rapamycin (mTOR). Available at:  

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895430/. Accessed May 1, 2020.

[vi] Interleukin-6 and C-reactive protein, successful aging, and mortality: the PolSenior study. Available at:

https://immunityageing.biomedcentral.com/articles/10.1186/s12979-016-0076-x. Accessed May 1, 2020.

[vii] Storci G, De Carolis S, Papi A, et al. Genomic stability, anti-inflammatory phenotype, and up-regulation of the RNAseH2 in cells from centenarians. Cell Death Differ. 2019 26(9):1845‐1858.

[viii] Can we use interleukin-6 (IL-6) blockade for coronavirus disease 2019 (COVID-19)-induced cytokine release syndrome (CRS)? Available at:

https://www.sciencedirect.com/science/article/pii/S0896841120300676#bib37. Accessed May 1, 2020.

[ix] Interleukin-6 blockade for severe COVID-19. Available at:  https://www.medrxiv.org/content/10.1101/2020.04.20.20061861v1. Accessed May 1, 2020.

[x] Into the Eye of the Cytokine Storm. Available at:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3294426/. Accessed May 1, 2020.

[xi] What Is The Cytokine Storm And Why Is It So Deadly For Coronavirus Patients? Available at:

https://www.forbes.com/sites/claryestes/2020/04/16/what-is-the-cytokine-storm-and-why-is-it-so-deadly-for-covid-19-patients/#52c3e224460f. Accessed May 1, 2020.

[xii] Chousterman BG, Swirski FK, Weber GF. Cytokine storm and sepsis disease pathogenesis. Semin Immunopathol. 2017 39(5):517‐528.

[xiii] Mohty M, Blaise D, Faucher C, et al. Inflammatory cytokines and acute graft-versus-host disease after reduced-intensity conditioning allogeneic stem cell transplantation. Blood. 2005;106(13):4407‐4411.

[xiv] COVID-19 infection and rheumatoid arthritis: Faraway, so close! Available at:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7102591/. Accessed May 1, 2020.

[xv] Controversies about COVID-19 and anticancer treatment with immune checkpoint inhibitors. Available at:

https://www.futuremedicine.com/doi/10.2217/imt-2020-0067. Accessed May 1, 2020.

[xvi] How does coronavirus kill? Clinicians trace a ferocious rampage through the body, from brain to toes. Available at:

https://www.sciencemag.org/news/2020/04/how-does-coronavirus-kill-clinicians-trace-ferocious-rampage-through-body-brain-toes. Accessed May 1, 2020.

[xvii] Coronavirus damages kidneys and hearts as well as lungs, US doctors find. Available at:

https://www.independent.co.uk/news/world/americas/coronavirus-symptoms-lung-kidney-heart-covid-19-us-doctors-a9466701.html. Accessed May 1, 2020.

[xviii] Tocilizumab for Treatment of Severe or Life-Threatening Chimeric Antigen Receptor T Cell-Induced Cytokine Release Syndrome—FDA Approval Summary. Available at:

https://www.bbmt.org/article/S1083-8791(17)30993-X/fulltext. Accessed May 1, 2020.

[xix] The cytokine release syndrome (CRS) of severe COVID-19 and Interleukin-6 receptor (IL-6R) antagonist Tocilizumab may be the key to reduce the mortality. Available at:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118634/. Accessed May 1, 2020.

[xx] Interleukin-6 blockade for severe COVID-19. Available at: https://www.medrxiv.org/content/10.1101/2020.04.20.20061861v1. Accessed May 1, 2020.

This article is a preprint and has not been certified by peer review [what does this mean?]. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.

Latest News