In a life-threatening illness when a patient develops a cytokine storm, it becomes a race to remove what will kill you versus the temporary inconvenience of removing things that your body manufactures all the time anyway. A treatment called Cytosorb (CTSO) can be applied to address this danger, as the New York Times has featured.
The U.S. Food and Drug Administration (FDA) has authorized the use of a cartridge, Cytosorb, that continually filters excess cytokines from the blood, similar to the way a dialysis machine removes toxins. The purified blood is then pumped back into the body.
To learn more about Cytosorb, Digital Journal spoke with Dr. Phillip Chan to learn more about the importance of the treatment in fighting COVID-19. Dr. Chan is the CEO of CytoSorbents.
Digital Journal: What is your take on the coronavirus pandemic?
Phillip Chan: The COVID-19 pandemic is a global tragedy that is far from over, particularly without a vaccine, oral antiviral therapy, or ubiquitous screening of asymptomatic patients that can prevent the spread of the disease. The terrible loss of life with more than a half a million deaths in more than 11 million documented infections worldwide so far, has been a wake-up call to the world community that infectious disease pandemics represent the most serious and recurrent threat to human life on this planet, far beyond that of nuclear annihilation, natural disasters, global warming, or pollution.
On top of the rise of multi-drug resistant bacteria, or “superbugs”, the greater threat is from easily communicable viruses like smallpox, Ebola, and many others. Perhaps the most feared is a highly contagious variant of H5N1 avian influenza, a virtual death sentence killing more than 60% of patients it infects. That said, ordinary seasonal flu can be devastating as well. Despite the wide availability of vaccines and oral-antiviral therapy, in the 2019-2020 flu season, the U.S. Centers of Disease Control and Prevention (CDC) estimates that up to 56 million Americans contracted the flu, leading to an estimated 410,000-740,000 hospitalizations, and up to 62,000 deaths.
Clearly vaccines and anti-viral therapies are important, but at the end of the day, are not the complete solution, particularly for those patients that develop life-threatening complications such as lung failure, shock, and sepsis. We must not forget innovative treatments designed to reduce the deadly cytokine storm and inflammation that may help the sickest COVID-19 patients recover, heal, and survive. An example is our CytoSorb® blood purification technology, currently approved in the European Union (EU) to treat cytokine storm, used in more than 88,000 treatments and distributed in 65 countries worldwide, and is now available in the U.S. under FDA Emergency Use Authorization for use in adult, critically-ill COVID-19 patients with imminent or confirmed respiratory failure.
DJ: What is a cytokine storm and why does this affect some patients?
Chan: The body produces more than 100 different cytokines – small proteins that normally help to orchestrate the immune response and to protect the body against injury and infection. With common names such as interleukins and interferons, these cytokines can either trigger or suppress inflammation, and typically work in synchrony to maintain immune system balance.
However, in life-threatening injury or infection (such as COVID-19), the immune system goes into overdrive, often resulting in the massive overproduction of cytokines, or “cytokine storm”, that drives widespread systemic inflammation, while directly killing cells, damaging vital organs like the lungs, heart, liver, and kidneys, and ultimately leading to death in many cases. The severity of cytokine storm varies in patients, and is often directly correlated with the severity of illness.
However, based on patients with genetic mutations that make them prone to a massive cytokine storm, such as familial hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS), there is likely to be a genetic predisposition that makes certain people more likely to develop a very severe and deadly response. That said, cytokine storm is very common, not just in life-threatening infections and sepsis (the overzealous immune response to infection) that is responsible for 1 in every 5 deaths worldwide, but can be seen in many patients in the ICU suffering from trauma, burn injury, complications of surgery, cytokine release syndrome from cancer immunotherapy, acute-on-chronic liver disease, severe acute pancreatitis, and many other conditions.
DJ: What is the history around blood purification?
Chan:Nearly 2,500 years ago, Hippocrates, the Greek father of modern medicine, advocated the removal of “evil humors” from the blood that caused disease. Throughout the centuries, this led to the popular use of bloodletting and leeches, which often harmed the patient more than it helped due to blood loss and shock. Then in the 19th century, the renowned chemist Thomas Graham revolutionized the concept of blood purification by proposing the use of a semi-permeable dialysis membrane to allow substances at high concentration in blood to diffuse across the dialysis membrane, into a solution where the substances are at low concentration, thereby purifying the blood with no blood loss. But it was not until 1913 that the technology was first reduced to practice in animals.
Then in 1924, Dr. George Haas dialyzed the first human patients and began the practice of heparin anticoagulation of blood, used widely today in dialysis. Though these cases were short and failed to provide benefit to patients, it led to the first successful long-term dialysis treatment in humans in 1945 by Dr. Willem Kolff. His system relied on a machine that wrapped dialysis tubing carrying blood from the patient around a large cylinder the size of an oil drum, and rotated the drum in a dialysate bath that allowed the flow of uremic toxins, such as urea and ammonia, from the blood into the dialysate, enabling longer and more effective treatment.
Today, the technology has matured where the hollow-fiber dialyzer is roughly the size of a tube of bathroom caulk and is very inexpensive. Dialysis, and the closely related technology, hemofiltration, are very good at removing small uremic toxins but are not effective at reducing cytokines and mid-sized inflammatory mediators. Our CytoSorb® cartridge is classified as a hemoperfusion device, the third most common category of blood purification, and is the first specifically approved extracorporeal cytokine adsorber in the European Union. Unlike dialysis or hemofiltration technologies that utilize dialysis membranes with only 1 to 3 square meters of surface area, each CytoSorb device is composed of millions of tiny porous polymer beads with approximately 7 football fields of surface area, giving the cartridge massive capacity to bind cytokines.
DJ: How can blood purification assist with treating COVID-19?
Chan:In COVID-19, cytokine storm is linked to patients with the worst organ failure and highest risk of death. Cytokine storm and other contributors to hyperinflammation, such as activated complement, can cause blood vessels to become injured. This can lead to capillary leak syndrome where fluid from the blood stream floods the air spaces of the lung, exacerbating viral pneumonia and essentially drowning the patient from the inside out. This leakage of fluid happens throughout the body, compromising oxygen exchange between organs and the blood, and contributes to widespread organ damage.
In addition, these inflammatory toxins can damage the lining of the blood vessel wall directly, leading to the formation of microscopic blood clots and a thrombotic microangiopathy in blood vessels. In autopsy lung specimens taken from deceased COVID-19 patients, these clots are dispersed throughout the lung, contributing to large sections of lung that no longer have blood flow and can no longer exchange oxygen, resulting in severe shortness of breath and low oxygen levels. This hypercoagulability, or tendency to clot, is very common in COVID-19 patients, and thought to be one of the reasons patients are so sick. Also, hyperinflammation can lead to hemodynamic instability and shock, a significant contributor to death in these patients.
CytoSorb has now been used in approximately 1,000 COVID-19 patients in more than 20 countries around the world, including the U.S. under FDA Emergency Use Authorization, to reduce cytokine storm and inflammatory mediators, such as activated complement, to help reduce the formation of blood clots, and stabilize critically-ill patients with complications of COVID-19 viral sepsis such as respiratory failure, shock, and kidney failure. Physicians are using CytoSorb right before patients need mechanical ventilation, shortly after going on mechanical ventilation, or when they fail mechanical ventilation and need to start extracorporeal membrane oxygenation (ECMO) – a machine that can oxygenate blood outside the body when the lungs become so diseased that mechanical ventilation no longer works. Physicians are reporting that CytoSorb has helped to keep a number of patients off of mechanical ventilation, and has helped to improve oxygenation and lung function, leading to the weaning of many patients off of mechanical ventilation and ECMO. In addition, a routine reduction in markers of inflammation such as C-reactive protein (CRP) and ferritin have been observed, as well as a reversal of shock in patients with very low blood pressure.
DJ: How does CytoSorb work?
Chan:The CytoSorb cartridge is filled with tiny porous polymer beads roughly the size of a grain of salt. Each of these beads has millions of pores and channels that allow the bead to act like a tiny sponge and remove cytokines and other inflammatory mediators of a certain size. Cells and antibodies are too large to get into the pores and go around the bead and are unaffected. Very small substances such as blood electrolytes go straight through the device and are unaffected. The beads are very efficient at removing cytokines, and can do so without the need for antibodies or other affinity agents.
Treatment is very simple because CytoSorb is plug-and-play into the existing blood pump infrastructure in most hospitals today. Set up is similar to dialysis, where blood is pumped out of the body with a dialysis, continuous renal replacement therapy (CRRT), or ECMO machine, through the CytoSorb cartridge, and back into the patient over and over again. Often referred to as a “Brita filter for your blood,” a single cartridge can treat a patient’s entire blood volume more than 70 times in a day. Each day, the CytoSorb cartridge is replaced with a new one. A COVID-19 patient typically receives at least 4 treatments.
DJ: Are there any risks with the treatment?
Chan:The therapy has been safe and well-tolerated in more than 88,000 human treatments in the European Union and abroad. Risks include those common to all extracorporeal (out of the body) blood therapies such as dialysis, including infection, blood loss, and removal of beneficial substances. For example, CytoSorb can result in a reduction in platelets, albumin, and some medications, such as certain antibiotics. However, antibiotics can be dosed to minimize the effect of CytoSorb removal, and the reduction of other substances is typically not clinically significant. In treating deadly cytokine storm, it is essential to reduce what is killing the patient as quickly as possible, provided the removal of other substances is not overtly harmful.
