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Exploring a New Weapon Against COVID-19 Cytokine Storm

Researchers have created an experimental device that, instead of inhibiting inflammatory proteins in COVID-19 patients, changes the phenotype of circulating white blood cells, helping wean two patients off ECMO.


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Stock. Credit: Getty Images.
Stock. Credit: Getty Images.

If we can implement a new therapy, we could save thousands of lives.” H. David Humes, M.D.

COVID-19 researchers have learned that excessive inflammation resulting from the virus’ “cytokine storm” in the body plays a critical role in the development of acute respiratory distress syndrome, or ARDS, a buildup of fluid in the lungs that causes breathing failure and low oxygen levels in the blood.

It’s the leading cause of death in affected patients because of consequential multi-organ failure.

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Efforts to combat this cytokine storm, or uncontrolled release of pro-inflammatory cytokines, have often proved unsuccessful in the sickest of COVID-19 patients. The clinical approach has typically been to try and lower cytokine activity or inflammatory levels with specific cytokine inhibitors.

But an experimental extracorpeal device used with ECMO (artificial lung support) uses a different mechanism of regulating cytokine-producing white blood cells that may halt organ damage and help wean patients off the lung support, according to findings in The American Society for Artificial Internal Organs Journal.

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The novel approach has so far successfully been used in two patients. But researchers say the outcomes hint the device could benefit others, turning COVID-19’s large inflammatory wildfire into small brush fires, providing time for the body to heal itself.

SEE ALSO: Keeping Our Patients Safe During COVID-19 https://www.uofmhealth.org/coronavirus/keeping-patients-safe

What is extracorporeal selective cytopheretic device therapy?

The extracorporeal selective cytopheretic device is an immunomodulatory therapy that’s been evaluated in several FDA-approved clinical trials in patients with excessive inflammation, including sepsis, acute kidney failure and ARDS. Studies suggest it is a safe and effective way to aid organ recovery and reduce mortality for those with multi-organ failure.

With FDA emergency-use approval for a subset of intensive care unit COVID-19 patients, the research team screened ICU patients and provided continuous device treatment for approximately two weeks for two qualifying patients on mechanical ventilation and ECMO.

“The device is a membrane that is integrated into a typical hemodialysis system, or renal replacement therapy blood circuit. As blood flows along the membranes within the device, the most activated white blood cells bind to the membrane and are altered to a less inflammatory phenotype,” says Lenar Yessayan, M.D., the study’s lead author and Michigan Medicine nephrologist who provided treatment to the study’s participants. “The white blood cells engage less in attacking the organs which tempers the cytokine storm and subsequent tissue damage.”

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But in order for the therapy to work, there needs to be a low ionized calcium environment. This is achieved by infusing citrate into the renal replacement therapy blood circuit. In this situation, the device provides a continuous process to lessen the inflammatory state of the circulating white blood cells and reduces the cytokine storm within the patient.

“This low calcium level occurs only in the circuit, but not in the patient’s blood. Replacement calcium is infused into the blood circuit exiting the system so that blood returning to the patient maintains a normal calcium level in their body,” says H. David Humes, M.D., the study’s senior author and another Michigan Medicine nephrologist involved in the emergency expanded use of this therapy.

For the two patients that received treatment, this unique device was provided along the ECMO blood circuit during the entire course of ECMO treatment since the optimal duration of therapy was, and is, still being evaluated.

Study results

The two patients that were enrolled in this study had COVID-19 associated ARDS requiring mechanical ventilation and ECMO support. Most notably, they had highly elevated levels of a protein that helps regulate the immune system (interleukin-6), indicating inflammation in the body.

“These patients were deteriorating quickly, so this device was a last ditch effort. They both had high expected mortality rates,” says Humes.

Patient one, a 26-year-old man, had interleukin-6 levels of 231 pg/mL. He was started on the device after three days on ECMO and within 52 hours, his blood oxygen levels improved with reduced need for supplemental oxygen.

His interleukin-6 levels were reduced to 3.32 pg/mL and other inflammatory markers (LDH, procalcitonin, C-reactive protein and D-dimer) were significantly reduced and trended to normal values while being weaned off ECMO. After 20 days on ECMO, and 17 with the device, he was taken off ECMO.

“This was wonderful for the patient and his family, but also for our physicians, nurses and other healthcare providers to see. It was a victory after losing so many battles against this virus in our ICU patients,” says Humes.

Patient two, a 52-year-old man, had several preexisting conditions putting them at risk for a significant COVID-19 illness, including history of diabetes, hypertension, chronic kidney disease and obesity. His severe ARDS and acute kidney failure required mechanical ventilation, ECMO and acute hemodialysis.

A little more than two days after the patient started with the device, his blood oxygen levels improved. Interleukin-6 and other inflammatory markers were also reduced, so much so that four days after the treatment, his ventilation settings were lowered.

The patient’s interleukin-6 levels continued to trend downward throughout the therapy, and oxygenation continued to improve while ECMO was being weaned. After 16 days of device use, he was taken off of ECMO and the device and discharged from the hospital after 21 days.

SEE ALSO: Seeking Medical Care During COVID-19 https://www.uofmhealth.org/coronavirus/seeking-medical-care-covid-19

Of particular interest to Yessayan and Humes’ team was the interleukin-6 to interleukin-10 ratios in the two patients, which declined from 11.8 and 18 to 0.7 and 0.62 respectively.

“A lower ratio of these two cytokines is a reliable marker to discern the severity of pneumonia. Ratios near one are associated with less disease,” says Yessayan. “There needs to be a large clinical trial to support these conclusions, but this therapy might give COVID-19 patients hope and a fighting chance to recover. We’re one step closer.”

Potential implications

The potential of this device to treat sick patients transcends from COVID-19 to anyone with a severe inflammatory disease, according to Yessayan and Humes.

The therapy was also recently used in 14 critically ill pediatric patients with severe acute kidney injury and multi-organ failure. The treatment successfully reduced the mortality in these children from 50 to 25%, and all survivors recovered kidney function with discontinuation of dialysis.

An FDA approved multi-center clinical trial is currently underway to evaluate the potential of the device to effectively treat COVID-19 ICU patients.

“If we can implement a new therapy, we could save thousands of lives,” says Humes.

Disclosures: The University of Michigan has licensed the extracorporeal selective cytopheretic device technology used for this trial to SeaStar Medical. The University may be paid royalties in the future if the investigational technology is shown to improve outcomes. Humes, as the inventor of the device, is also entitled to royalties. The University and Humes are part-owners of SeaStar. For this study, Humes is participating in this research at the company but not in his University role.

Paper cited: “Treatment of Cytokine Storm in COVID-19 Patients with Immunomodulatory Therapy,” ASAIO Journal. DOI: 10.1097/MAT.0000000000001239


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