Potential Deadly Role of Elevated IL-6 in Severe COVID-19 Disease

The primary “cytokine storm” culprit appears to be interleukin-6 (IL-6).

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

Relevant Links: 1, 2, 3. 

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.

Link to study: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3876432/

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.

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. 

Rationale to Test IL-6 Blood Levels if Symptomatic

Update: A recent study shows a wide range of inflammatory biomarkers are all significantly associated with increased ICU admission, intubation and death

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.

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)?”

Link to study: https://www.sciencedirect.com/science/article/pii/S0896841120300676#bib37

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.

Link to study: https://www.medrxiv.org/content/10.1101/2020.04.20.20061861v1

 

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.

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.

Link to study: https://www.sciencedirect.com/science/article/pii/S0896841120300676#bib37

 

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.”

 

Melatonin Highlighted for Multi-modal Covid-19 Treatment Potential

The World Health Organization recently added melatonin to its database as a supplementary treatment option for Covid-19 patients, for its laundry list of potential benefits, of which IL-6 mitigation is included. 

 

Among other benefits, melatonin has shown to be effective in curbing inflammation, oxidation, and an exaggerated immune response. In conjunction, these factors encompass a significant component of the overall functional cause of mortality by Covid-19. 

Read the full study here.

 

Clinical Use of an IL-6 Signaling Blocking Drug

Critical Update - Actemra and Kevzara, two distinct IL-6 targeting drugs were recently found to be ineffective in reducing Covid-19 mortality in two individual clinical trials studying them. More info here.

 

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.

Link to study: https://www.bbmt.org/article/S1083-8791(17)30993-X/fulltext

 

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

Link to study: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118634/

 

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”.

Link to study: https://www.bbmt.org/article/S1083-8791(17)30993-X/fulltext

 

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.

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.

Clinical Trials Currently Recruiting That Analyze

Actemra® (Tocilizumab) Effects in COVID-19 Patients

 

 

 

 

 

 

 

-Use Green Scroll Bar on Upper Right Corner to View All Studies-

Many other IL-6 mitigating drugs are currently slated for clinical trials. You can view the status of drugs that interest you at 

https://clinicaltrials.gov/

 Prazosin for Treatment of Cytokine Release Syndrome

A continued review of potential drug repurposing opportunities given the lack of safe and effective treatment options currently available for COVID-19/SARS-CoV-2 has uncovered a new review published on the potential use of prazosin, an alpha-adrenergic blocking Rx commonly prescribed for BPH, in aging men in cytokine release syndrome/“cytokine storm” associated with COVID-19.

 

Infections are associated with catecholamine release and catecholamines enhance inflammatory damage by increasing the production of IL-6 and other cytokines by immune cells. This process requires alpha-1 adrenergic receptor (alpha-1 AR) signaling to occur. 

The authors cited a preclinical study that showed inhibition of catecholamine synthesis with metyrosine, a tyrosine hydroxylase antagonist, caused reduced levels of catecholamines and cytokine responses which resulted in significantly increased survival in mice.Similar protection against hyperinflammatory stimulus was observed with the well-tolerated ⍺1-AR antagonist, prazosin, (but not beta-adrenergic receptor antagonists).

The authors also cited a preliminary, recent retrospective clinical study in hospitalized patients diagnosed with pneumonia or acute respiratory distress, the likelihood of requiring mechanical ventilation and dying was significantly lower if patients were taking alpha-1 AR antagonists, like prazosin, during the year preceding hospitalization.

Link to Study: https://www.jci.org/articles/view/139642/pdf

BTK Inhibitors May Help Treat Monocyte/Macrophage Activation and Associated Hyper-Inflammatory Cytokine Storm

A very intriguing, new prospective study shows interesting results for a small sample size of patients who have severe COVID-19 treated with a BTK inhibitor.

 

Activation of BTK and production of IL-6 was detected in COVID-19-infected monocytes.

The drug acalabrutinib, a selective BTK inhibitor, was administered off-label to 19 patients hospitalized with severe COVID-19 (11 on supplemental oxygen; 8 on mechanical ventilation), 18 of whom had increasing oxygen requirements at baseline.


Over a 10-14 day treatment course, acalabrutinib improved oxygenation in a majority of patients, often within 1-3 days, and had no discernable toxicity.
 

In addition to this, C-reactive protein and IL-6 normalized quickly in most patients, as did lymphopenia, in correlation with improved oxygenation.

At the end of the acalabrutinib treatment, 8/11 (72.7%) patients in the supplemental oxygen cohort had been discharged on room air, and 4/8 (50%) patients in the mechanical ventilation cohort had been successfully extubated, with 2/8 (25%) discharged on room air. 

Link to Study: https://immunology.sciencemag.org/content/5/48/eabd0110.full

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.

 

Link to Study: ​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.

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.”

Link to Study: https://www.medrxiv.org/content/10.1101/2020.04.20.20061861v1

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