I would say there are few people in the nation who can synthesize complex aggregate health care data sets as well as this guy. He was one of the top Milliman actuaries in the country. Here is a link to Milliman's website:https://www.milliman.com/en/health
Here are some thoughts he sent to me. This is very long, and he feels very strongly that the approach we have taken has been way off. Many of you will not like what he thinks should happen. To sum it up, he's pretty much in the Dr. Scott Atlas' camp as I read all the stuff he's sent me. I have NO idea of his politics. I have not talked to this guy for quite some time and I have never talked politics with him ever. Here are his thoughts. Again, this is very long.
I have a client called Agilum that is a data aggregator, specifically of inpatient hospital data associated with 340b administration done by a sister company called Sentry Data Systems. They are trying to kick-start the brand recognition around their data. I began to think about ways to do that and focused on making some contribution to Covid 19 based upon nationwide real world data (RWD). The only Covid metric at this point appears to me mortality. I think it is pretty clear that the disease seems to be opportunistic to a certain demographic, primarily frail elderly patients with co-morbidities. The biggest catastrophe to date is the inhumane dereliction of responsibility to protect nursing home patients. By chance, I read a WSJ opinion piece interviewing Michael Milkin a few weeks ago. Milkin’s focus is cancer and he noted a particular passion for drugs that address cytokine issues. I was not too familiar with cytokines so I started to read and haven’t stopped since.
Did I ever open up a can of worms. Dating back to 2014 Scripps Institute was starting to connect the causes of the most severe morbidity and mortality to cytokine release syndrome (CRS), which is morphing into cytokine storm syndrome (CSS). Scripps attributed the majority of deaths due to annual influenza, as far back as the Spanish Flu, to CRS/CSS. I am no clinical expert, although a physician client once asked (not really in jest), where I did my training. I do still work closely with my former physician consultant and we compare notes a lot. It seemed that there needs to be some awareness in the practicing community and a research paper with descriptive statistics discussing the most severe morbidity and mortality. I am working to that end with Agilum. The basic thesis is dealing with septic shock and reviewing RWD isolating the patient illness journey when controlling for certain variables. The concept is to produce RDW descriptive statistics around mortality that may lead to some consensus action.
Although there seems to be a lot of research knowledge related to the origins of high mortality and morbidity risk associated with annual influenza, there doesn’t seem to be a lot of common awareness among practicing professionals. For example, physicians continue to be reactive rather than proactive around patients that suffer sudden drop-off and deterioration. Respirator patients tend to have extremely high mortality, nearly 90% in New York. Also pediatricians seemed to have been caught off guard by select pediatric occurrences of Kawasaki-like rheumatic disease in Covid 19 patients, an inflammatory disease that may be rooted in CRS/CSS.
SUMMARY COVID LEARNINGS (PERHAPS REDUNDANT FOR PROFESSIONALS)
The current Covid 19 pandemic has some interesting emerging data. It primarily affects the elderly and frail most severely. Possibly up to 15% - 20% of infected patients are severe and critical. A small percent of infected pediatric patients experience symptoms of Kawasaki’s disease. Research on influenza dating back to 2014 has focused on the origins of high mortality and morbidity risk associated with annual influenza and what drives the incidence. A common research thread points CRS/CSS. CRS and CSS are used interchangeably in clinical literature. CRS/CSS is defined as an immune response. Cytokines are a group of proteins made by the immune system that act as chemical messengers. They serve as the immune system’s reconnaissance team identifying enemy cells that other immune chemicals attack. In normal immune systems, proteins will punch a hole in the enemy cells flagged by the cytokines and pour in toxic chemicals that induces the enemy cells to self-destruct.
In normal viral infections, most commonly the annual flu, cytokines create a healthy and beneficial inflammatory response as long as the cytokines remain in check. For most humans, the cytokine response remains in check. The problem occurs when the cytokines are unchecked. When cytokines are unchecked, the body suffers from CRS/CSS and can lead to several severe reactions such as vascular leakage, microvascular thrombosis, organ failure, cardiac failure, kidney failure, deep vein thrombosis, and strokes. A quote from the WSJ last Friday, entitled Coronavirus Hijacks the Body From Head to Toe, Perplexing Doctors is enlightening:
The virus’s strange effects go beyond anything doctors say they usually see with other viral infections. “It seems to strike so many systems,” said Maya Rao, a nephrologist at New York-Presbyterian/Columbia University Irving Medical Center in New York who is treating Covid-19 patients with acute kidney failure. “We don’t understand who gets it.” Doctors are trying to understand what about the infection predisposes patients to so many complications.
Clinical research would indicate that patients, such as that described above, are suffering from CRS/CSS. One may ask why Dr. Rao, for example, is not aware of CRS/CSS? This is quite common in the practice of medicine, particularly when a specialist consult (kidney specialist in this case) is asked to manage kidney function. So much focus is on the kidneys that they sometime cannot grasp the bigger picture. Also, when physicians are in the moment dealing with a crisis, there is not a nice RWD summary from which to compare notes and consider.
CONFIRMATORY AUTOPSIES
Scripps Institute published a peer reviewed article back in 2014 stating that CRS/CSS plays a direct role in the morbidity and mortality from influenza virus infection. In other words, CRS/CSS was the cause of death rather than the virus itself. Antiviral drugs are effective against the virus but not against CRS/CSS or technically what is called an immune-mediated injury. Only a fraction of infected people become desperately and sometimes mysteriously ill. “The real morbidity and mortality of this disease is probably driven by this out of proportion inflammatory response to the virus,” says Jamie Garfield, a pulmonologist who cares for COVID-19 patients at Temple University Hospital.
A direct result of CRS/CSS is that blood vessels leak, blood pressure drops, clots form, and catastrophic organ failure ensues. A pathologist is Switzerland has performed autopsies on 21 of the 50 total deaths that occurred in Switzerland (article attached) and is documenting clotting issues in deceased patients. Each autopsy provided the same common clinical indication:
“The disease takes place in the smallest vessels in the lungs and in other organs. If these vessels can no longer function properly, clots form”, explains Tzankov. Because it is their job to keep the blood liquid. Due to the blockage of the bloodstream, the blood is now practically still. “If the patient is now ventilated, the oxygen gets into the blood, but is no longer distributed in the body,” says Tzankov. This ultimately leads to death – as happened with the 21 patients who the pathologists from the region examined after their death. However, only a few would have shown signs of pneumonia.
A study of autopsy findings of the first 12 patients who died of COVID-19 in a hospital in Hamburg, Germany, has found that 7 (58%) of them had undiagnosed deep vein thrombosis, suggesting that the virus may cause abnormal blood clotting.
WebMD reports similar anecdotal trends.
Around the world, doctors caring for COVID-19 patients have been trying to make sense of the same thing. When they draw blood from COVID patients, it clots in the tubes. When nurses insert catheters for kidney dialysis and IV lines to draw blood, the tubes quickly become clogged with clots. “Patients are making clots all over the place,” says Adam Cuker, MD, a hematologist and associate professor of medicine at the Hospital of the University of Pennsylvania. “That’s making management of these patients very challenging.”
AN ALTERNATIVE WAY TO ADDRESS COVID 19
An alternative way to address Covid 19 and the true morbidity and mortality of Covid 19 may rely less on testing for Covid 19 or antibody testing. I have spent a career stressing data driven probabilistic management of risk. Resources are limited. You cannot conceivably manage all risk, so the focus needs to be upon the most severe risks with the highest likelihood of occurrence. That same strategy can be applied to Covid 19. The normal course of Covid 19 can be asymptomatic or relatively benign. The true morbidity and mortality of Covid 19 appears to be CRS/CSS. Articles discuss the Covid cliff that they look for after about 13 days post infection. As such, address Covid 19 by focusing on the greatest risk for high mortality and morbidity. The basic tactics are:
· Public Health Screening. Develop a public health screening protocol to assess the risk of CRS/CSS and potentially faux rheumatic diseases like Kawasaki’s. The purpose is to identify potential high-risk patients should they become infected by Covid 19. A current intense discussion surrounds opening schools. While pediatric and young adults have extremely low Covid 19 severity, critics quickly point to the small percentage of pediatric patients with hyper-inflammatory reactions similar to Kawasaki’s. A screening tool to identify at-risk individuals could be applied by the “school nurse” to flag students for simple blood testing that will be able to confirm the high risk status and further preventive measures.
· Blood Testing Protocol. Simple and available blood tests are recommended for individuals flagged by public screening. Various conventional tests are being recommended to assess CRS/CSS risk. D-dimer, PT, aPTT, and fibrinogen level assays are being recommended to assess clotting risk. Tests of serum ferritin can also provide indications of clot risk due to high levels of iron. These tests provide clot risk assessment in patients with Covid 19 and are highly recommended to identify risk for CRS/CSS. Patients with Types A or B blood seem to pose highest hemostasis.
· Consensus Based Treatment Protocols. Some basic practice protocols seem to be emerging regarding early identification and treatment of CRS/CSS. Such protocols include screening of patients admitted to the hospital with suspected Covid 19 (with identification of patients already receiving anticoagulant therapy as part of chronic care management); series of genetic and blood tests to identify CRS/CSS risk for suspected patients (due to screening process); assignment of hematology, rheumatology, immunology, and vascular specialists to patients with elevated CRS/CSS risk; consideration of prophylaxis and therapeutic anticoagulation in high risk patients with COVID-19 without confirmed/suspected thrombosis; and consideration of early, aggressive treatment with immunomodulatory agents, with or without the combination of antivirals. The American College of Cardiology (attached) has already issued recommendations associated with thrombosis (blood clotting) and Covid 19. The University of Miami has also been very proactive in publishing guidelines to assess and treat the highest risk Covid patients (attached).
MY INTERESTS
My primary interest, aside from the client request, is to understand efficacious Covid 19 protocols in case I become infected. I am a potential high risk patient and I want to understand my personal choices if I happen to suffer from CRS/CSS. This includes assessment of risk and prophylactic treatments to deal with both the infectious and vascular risks from Covid 19.
I am not at all on the remdesivir bandwagon. The clinical trials bent a number of statistical rules for hypothesis testing as well as some changes were made to study design that I cannot tell whether were done prior to original test design or after. I also thought the differences were not significantly different for mortality. Finally, this drug has been laying around for over 10 years looking for a clinical home. I am a skeptic that Dr. Fauci had some vested interest in promoting the drug as quickly as he did. Also, Gilead had ramped up production and I am skeptical that promises may have been made to guarantee the return on investment. Finally, it fails to address the CRS/CSS risk.
I should note that earlier tonight I was with one of my nieces who is the night NP hospitalist at our local hospital. She has been in the middle of this since day one as she is the frontline person at our hospital from 7p to 7A 7 days off 7 days on. She said that roughly 30% of all the CV IP's they have had have been readmitted and every single one of them has been readmitted for coagulation issues.
Finally here is an email he sent to Dr. Bruce Patterson, who was one if not the first MD's to posit the Rantes' theory as the culprit that is impacting the moderately to severly ill CV patients:
The email exchange between Tony and me. I make the comment that the only metric for Covid 19 driving all discussion is death. With such emphasis, I thought about working backward from death to try to understand what about a flu virus causes death. That is where I began with the concept of septic shock and what happens in bodily systems and what are the causes. A lay person like me can understand the concept of microvascular pus balls ravaging the internal system. While normal infections can affect older patients and cause death, the majority that end in septic shock suffer from CRS/CSS. There is a lot of knowledge about CRS/CSS, but it seems to lack awareness. I mention in the email that follows, I stumbled on this trying to help a client trying to exploit their robust database to understand Covid 19. I am working with them to create descriptive statistics that describe the disease journey of Covid 19 patients. The concept is to isolate potential clinical and demographic markers associated with different journeys and trying to get that information into the public domain. I would be interested in working with you (we are also approaching the University of Miami and are interested in both institutions contributing) to review and provide insight on the analysis. Milliman, my old firm, will be providing statistical and technical counsel as part of the work product, which is intended to be an article discussing an application of real world data delivered in a timely fashion. The time lag for my client is about a week, not years.
The longer strategy is to get the notice of professional societies (like the College of Cardiology and attached) to devise some emergency patient management protocols focused on patients with the highest probability for significant morbidity and mortality. Can we identify high risk patients early in their journey so that prophylaxis and early interventions can be made before the patient succumbs to septic shock or CRS/CSS.
I have learned a lot talking to these two guys and thought you might find this interesting.
Here are some thoughts he sent to me. This is very long, and he feels very strongly that the approach we have taken has been way off. Many of you will not like what he thinks should happen. To sum it up, he's pretty much in the Dr. Scott Atlas' camp as I read all the stuff he's sent me. I have NO idea of his politics. I have not talked to this guy for quite some time and I have never talked politics with him ever. Here are his thoughts. Again, this is very long.
I have a client called Agilum that is a data aggregator, specifically of inpatient hospital data associated with 340b administration done by a sister company called Sentry Data Systems. They are trying to kick-start the brand recognition around their data. I began to think about ways to do that and focused on making some contribution to Covid 19 based upon nationwide real world data (RWD). The only Covid metric at this point appears to me mortality. I think it is pretty clear that the disease seems to be opportunistic to a certain demographic, primarily frail elderly patients with co-morbidities. The biggest catastrophe to date is the inhumane dereliction of responsibility to protect nursing home patients. By chance, I read a WSJ opinion piece interviewing Michael Milkin a few weeks ago. Milkin’s focus is cancer and he noted a particular passion for drugs that address cytokine issues. I was not too familiar with cytokines so I started to read and haven’t stopped since.
Did I ever open up a can of worms. Dating back to 2014 Scripps Institute was starting to connect the causes of the most severe morbidity and mortality to cytokine release syndrome (CRS), which is morphing into cytokine storm syndrome (CSS). Scripps attributed the majority of deaths due to annual influenza, as far back as the Spanish Flu, to CRS/CSS. I am no clinical expert, although a physician client once asked (not really in jest), where I did my training. I do still work closely with my former physician consultant and we compare notes a lot. It seemed that there needs to be some awareness in the practicing community and a research paper with descriptive statistics discussing the most severe morbidity and mortality. I am working to that end with Agilum. The basic thesis is dealing with septic shock and reviewing RWD isolating the patient illness journey when controlling for certain variables. The concept is to produce RDW descriptive statistics around mortality that may lead to some consensus action.
Although there seems to be a lot of research knowledge related to the origins of high mortality and morbidity risk associated with annual influenza, there doesn’t seem to be a lot of common awareness among practicing professionals. For example, physicians continue to be reactive rather than proactive around patients that suffer sudden drop-off and deterioration. Respirator patients tend to have extremely high mortality, nearly 90% in New York. Also pediatricians seemed to have been caught off guard by select pediatric occurrences of Kawasaki-like rheumatic disease in Covid 19 patients, an inflammatory disease that may be rooted in CRS/CSS.
SUMMARY COVID LEARNINGS (PERHAPS REDUNDANT FOR PROFESSIONALS)
The current Covid 19 pandemic has some interesting emerging data. It primarily affects the elderly and frail most severely. Possibly up to 15% - 20% of infected patients are severe and critical. A small percent of infected pediatric patients experience symptoms of Kawasaki’s disease. Research on influenza dating back to 2014 has focused on the origins of high mortality and morbidity risk associated with annual influenza and what drives the incidence. A common research thread points CRS/CSS. CRS and CSS are used interchangeably in clinical literature. CRS/CSS is defined as an immune response. Cytokines are a group of proteins made by the immune system that act as chemical messengers. They serve as the immune system’s reconnaissance team identifying enemy cells that other immune chemicals attack. In normal immune systems, proteins will punch a hole in the enemy cells flagged by the cytokines and pour in toxic chemicals that induces the enemy cells to self-destruct.
In normal viral infections, most commonly the annual flu, cytokines create a healthy and beneficial inflammatory response as long as the cytokines remain in check. For most humans, the cytokine response remains in check. The problem occurs when the cytokines are unchecked. When cytokines are unchecked, the body suffers from CRS/CSS and can lead to several severe reactions such as vascular leakage, microvascular thrombosis, organ failure, cardiac failure, kidney failure, deep vein thrombosis, and strokes. A quote from the WSJ last Friday, entitled Coronavirus Hijacks the Body From Head to Toe, Perplexing Doctors is enlightening:
The virus’s strange effects go beyond anything doctors say they usually see with other viral infections. “It seems to strike so many systems,” said Maya Rao, a nephrologist at New York-Presbyterian/Columbia University Irving Medical Center in New York who is treating Covid-19 patients with acute kidney failure. “We don’t understand who gets it.” Doctors are trying to understand what about the infection predisposes patients to so many complications.
Clinical research would indicate that patients, such as that described above, are suffering from CRS/CSS. One may ask why Dr. Rao, for example, is not aware of CRS/CSS? This is quite common in the practice of medicine, particularly when a specialist consult (kidney specialist in this case) is asked to manage kidney function. So much focus is on the kidneys that they sometime cannot grasp the bigger picture. Also, when physicians are in the moment dealing with a crisis, there is not a nice RWD summary from which to compare notes and consider.
CONFIRMATORY AUTOPSIES
Scripps Institute published a peer reviewed article back in 2014 stating that CRS/CSS plays a direct role in the morbidity and mortality from influenza virus infection. In other words, CRS/CSS was the cause of death rather than the virus itself. Antiviral drugs are effective against the virus but not against CRS/CSS or technically what is called an immune-mediated injury. Only a fraction of infected people become desperately and sometimes mysteriously ill. “The real morbidity and mortality of this disease is probably driven by this out of proportion inflammatory response to the virus,” says Jamie Garfield, a pulmonologist who cares for COVID-19 patients at Temple University Hospital.
A direct result of CRS/CSS is that blood vessels leak, blood pressure drops, clots form, and catastrophic organ failure ensues. A pathologist is Switzerland has performed autopsies on 21 of the 50 total deaths that occurred in Switzerland (article attached) and is documenting clotting issues in deceased patients. Each autopsy provided the same common clinical indication:
“The disease takes place in the smallest vessels in the lungs and in other organs. If these vessels can no longer function properly, clots form”, explains Tzankov. Because it is their job to keep the blood liquid. Due to the blockage of the bloodstream, the blood is now practically still. “If the patient is now ventilated, the oxygen gets into the blood, but is no longer distributed in the body,” says Tzankov. This ultimately leads to death – as happened with the 21 patients who the pathologists from the region examined after their death. However, only a few would have shown signs of pneumonia.
A study of autopsy findings of the first 12 patients who died of COVID-19 in a hospital in Hamburg, Germany, has found that 7 (58%) of them had undiagnosed deep vein thrombosis, suggesting that the virus may cause abnormal blood clotting.
WebMD reports similar anecdotal trends.
Around the world, doctors caring for COVID-19 patients have been trying to make sense of the same thing. When they draw blood from COVID patients, it clots in the tubes. When nurses insert catheters for kidney dialysis and IV lines to draw blood, the tubes quickly become clogged with clots. “Patients are making clots all over the place,” says Adam Cuker, MD, a hematologist and associate professor of medicine at the Hospital of the University of Pennsylvania. “That’s making management of these patients very challenging.”
AN ALTERNATIVE WAY TO ADDRESS COVID 19
An alternative way to address Covid 19 and the true morbidity and mortality of Covid 19 may rely less on testing for Covid 19 or antibody testing. I have spent a career stressing data driven probabilistic management of risk. Resources are limited. You cannot conceivably manage all risk, so the focus needs to be upon the most severe risks with the highest likelihood of occurrence. That same strategy can be applied to Covid 19. The normal course of Covid 19 can be asymptomatic or relatively benign. The true morbidity and mortality of Covid 19 appears to be CRS/CSS. Articles discuss the Covid cliff that they look for after about 13 days post infection. As such, address Covid 19 by focusing on the greatest risk for high mortality and morbidity. The basic tactics are:
· Public Health Screening. Develop a public health screening protocol to assess the risk of CRS/CSS and potentially faux rheumatic diseases like Kawasaki’s. The purpose is to identify potential high-risk patients should they become infected by Covid 19. A current intense discussion surrounds opening schools. While pediatric and young adults have extremely low Covid 19 severity, critics quickly point to the small percentage of pediatric patients with hyper-inflammatory reactions similar to Kawasaki’s. A screening tool to identify at-risk individuals could be applied by the “school nurse” to flag students for simple blood testing that will be able to confirm the high risk status and further preventive measures.
· Blood Testing Protocol. Simple and available blood tests are recommended for individuals flagged by public screening. Various conventional tests are being recommended to assess CRS/CSS risk. D-dimer, PT, aPTT, and fibrinogen level assays are being recommended to assess clotting risk. Tests of serum ferritin can also provide indications of clot risk due to high levels of iron. These tests provide clot risk assessment in patients with Covid 19 and are highly recommended to identify risk for CRS/CSS. Patients with Types A or B blood seem to pose highest hemostasis.
· Consensus Based Treatment Protocols. Some basic practice protocols seem to be emerging regarding early identification and treatment of CRS/CSS. Such protocols include screening of patients admitted to the hospital with suspected Covid 19 (with identification of patients already receiving anticoagulant therapy as part of chronic care management); series of genetic and blood tests to identify CRS/CSS risk for suspected patients (due to screening process); assignment of hematology, rheumatology, immunology, and vascular specialists to patients with elevated CRS/CSS risk; consideration of prophylaxis and therapeutic anticoagulation in high risk patients with COVID-19 without confirmed/suspected thrombosis; and consideration of early, aggressive treatment with immunomodulatory agents, with or without the combination of antivirals. The American College of Cardiology (attached) has already issued recommendations associated with thrombosis (blood clotting) and Covid 19. The University of Miami has also been very proactive in publishing guidelines to assess and treat the highest risk Covid patients (attached).
MY INTERESTS
My primary interest, aside from the client request, is to understand efficacious Covid 19 protocols in case I become infected. I am a potential high risk patient and I want to understand my personal choices if I happen to suffer from CRS/CSS. This includes assessment of risk and prophylactic treatments to deal with both the infectious and vascular risks from Covid 19.
I am not at all on the remdesivir bandwagon. The clinical trials bent a number of statistical rules for hypothesis testing as well as some changes were made to study design that I cannot tell whether were done prior to original test design or after. I also thought the differences were not significantly different for mortality. Finally, this drug has been laying around for over 10 years looking for a clinical home. I am a skeptic that Dr. Fauci had some vested interest in promoting the drug as quickly as he did. Also, Gilead had ramped up production and I am skeptical that promises may have been made to guarantee the return on investment. Finally, it fails to address the CRS/CSS risk.
I should note that earlier tonight I was with one of my nieces who is the night NP hospitalist at our local hospital. She has been in the middle of this since day one as she is the frontline person at our hospital from 7p to 7A 7 days off 7 days on. She said that roughly 30% of all the CV IP's they have had have been readmitted and every single one of them has been readmitted for coagulation issues.
Finally here is an email he sent to Dr. Bruce Patterson, who was one if not the first MD's to posit the Rantes' theory as the culprit that is impacting the moderately to severly ill CV patients:
The email exchange between Tony and me. I make the comment that the only metric for Covid 19 driving all discussion is death. With such emphasis, I thought about working backward from death to try to understand what about a flu virus causes death. That is where I began with the concept of septic shock and what happens in bodily systems and what are the causes. A lay person like me can understand the concept of microvascular pus balls ravaging the internal system. While normal infections can affect older patients and cause death, the majority that end in septic shock suffer from CRS/CSS. There is a lot of knowledge about CRS/CSS, but it seems to lack awareness. I mention in the email that follows, I stumbled on this trying to help a client trying to exploit their robust database to understand Covid 19. I am working with them to create descriptive statistics that describe the disease journey of Covid 19 patients. The concept is to isolate potential clinical and demographic markers associated with different journeys and trying to get that information into the public domain. I would be interested in working with you (we are also approaching the University of Miami and are interested in both institutions contributing) to review and provide insight on the analysis. Milliman, my old firm, will be providing statistical and technical counsel as part of the work product, which is intended to be an article discussing an application of real world data delivered in a timely fashion. The time lag for my client is about a week, not years.
The longer strategy is to get the notice of professional societies (like the College of Cardiology and attached) to devise some emergency patient management protocols focused on patients with the highest probability for significant morbidity and mortality. Can we identify high risk patients early in their journey so that prophylaxis and early interventions can be made before the patient succumbs to septic shock or CRS/CSS.
I have learned a lot talking to these two guys and thought you might find this interesting.
