COVID19, April 15, 2020 update: Cytokine storm — the immune system “killing the patient in order to save him/her”

The more I read about the (fairly rare) cases of younger people in generally good health dying or becoming critically ill, the more it sounded to me like “cytokine storm”, a.k.a. https://en.wikipedia.org/wiki/Cytokine_release_syndrome

In plain English, this is what happens when the immune system massively overreacts and does more damage to the patient than the original disease. It is generally assumed that the vast majority of deaths due to the 1918 “Spanish” Flu [*] resulted from cytokine storm, which explains the (for a flu) anomalous age distribution of mortality.

A reader (thanks a lot, Lissa!) forwarded me a story from the San Diego Union Tribune about a doctor in the prime of his life who got infected caring for the first major outbreak in Washington State.  https://archive.is/YBqAq

A 6-foot-3, 250-pound former football star who played for Northwestern in the 1996 Rose Bowl, he wasn’t fazed by much.

“To worry about myself, as a 44-year-old healthy man, didn’t even cross my mind,” he said in an interview Monday.

But on March 12, with his wedding day two months away, Padgett became the patient.

Soon after being admitted to his own hospital with a fever, cough and difficulty breathing, he was placed on a ventilator. Five days after that, his lungs and kidneys were failing, his heart was in trouble, and doctors figured he had a day or so to live.

He owes his survival to an elite team of doctors who tried an experimental treatment pioneered in China and used on the sickest of all COVID-19 patients.

Lessons from his dramatic recovery could help doctors worldwide treat other extremely ill COVID-19 patients.

“This is a movie-like save, it doesn’t happen in the real world often,” Padgett said. “I was just a fortunate recipient of people who said, ‘We are not done. We are going to go into an experimental realm to try and save your life.’”

Once his colleagues at EvergreenHealth realized they had run out of options, they called Swedish Medical Center, one of two Seattle hospitals that has a machine known as an ECMO, which replaces the functions of the heart and lungs.

But even after the hospital admitted him, doctors there had to figure out why he was so profoundly sick.

Based on the astronomical level of inflammation in his body and reports written by Chinese and Italian physicians who had treated the sickest COVID-19 patients, the doctors came to believe that it was not the disease itself killing him but his own immune system.

It had gone haywire and began to attack itself — a syndrome known as a “cytokine storm.”

The immune system normally uses proteins called cytokines as weapons in fighting a disease. For unknown reasons in some COVID-19 patients, the immune system first fails to respond quickly enough and then floods the body with cytokines, destroying blood vessels and filling the lungs with fluid.

The doctors tried a drug called Actemra [US brand name for the immunosuppressor https://en.wikipedia.org/wiki/Tocilizumab] which was designed to treat rheumatoid arthritis [an autoimmune disease] but also approved in 2017 to treat cytokine storms in cancer patients.

“Our role was to quiet the storm,” said Dr. Samuel Youssef, a cardiac surgeon. “Dr. Padgett was able to clear the virus” once his immune system was back in balance.

Dr. Matt Hartman, a cardiologist, said that after four days on the immunosuppressive drug, supplemented by high-dose vitamin C and other therapies, the level of oxygen in Padgett’s blood improved dramatically. On March 23, doctors were able to take him off life support.

Four days later, they removed his breathing tube. He slowly came out of his sedated coma, at first imagining that he was in the top floor of the Space Needle converted to a COVID ward.

There are a number of theories why chloroquine and hydroxychloroquine (HOcq) appear to have at least to some therapeutic benefit in COVID-19 patients: one that it is a zinc metallophore and zinc interferes with RdRa (RNA-dependent RNA polymerase, the enzyme that makes copies of the viral genome); another that it changes the intracellular pH to an extent that interferes with viral reproduction; yet another that it has some protective effect on hemoglobin. But the real answer may have been staring us in the face all the time:  HOcq, aside from being a decades-old antimalarial, also happens to be a mild immunosuppressant, and has been used as such (initially off-label) for many years (under the US brand name Plaquenil) in patients with autoimmune diseases like lupus and rheumatoid arthritis. So its real benefit may be in holding cytokine storm at bay, and stopping the immune system from “killing the patient in order to save him/her”. 

Now a downregulated immune system will result in greater vulnerability to opportunistic bacterial superinfections — which is why the simultaneous administration of an antibiotic like azithromycin (“Z-pak” as it’s popularly known in the US) appears to give added value to the treatment. As for the recommendation of adding zinc: I already commented on that yesterday.

As I am writing these lines, it occurred to me that cytokine storm and “killing the patient in order to save him/her” may be perfect metaphors for extended (6-months and more) economic shutdowns that are sure to kill or irreparably damage an economy. I am perhaps the last person on the planet to dispute the usefulness of lockdowns and social distancing measures where appropriate. My own country has applied them severely, but this makes complete sense given our population density. They should not be applied as blunt instruments in a one-size-fits-all approach, and (at least this is widely discussed here) cannot be kept up for more than a limited time.  To give an example: applying the same standards across a continent-sized country, whether it is thinly populated Wyoming or teeming New York City, makes no sense. New York City and its commuter counties in adjacent states New Jersey and Connecticut account for nearly half the new cases AND mortality in the US — it was pointed out to me by my friend David S. Bernstein that the hardest-hit counties proportionally are not Manhattan (as one might naively expect based on population density) but the commuter counties. I can hardly think of a riskier prospect in a major respiratory epidemic than having to commute half an hour or an hour each way packed like sardines in a subway. (As far as I can tell from the New York Municipal Transit Authority website, the subway is still running, albeit with reduced service.) The same people who would want to apply the “if it only saves one life” standard to justify asinine measures like prohibiting the sale of seeds and gardening tools in Michigan supermarkets should instead direct their energies to New York City — where public transportation is likely responsible for more infections than all the “nonessential purchases” in the rest of the country combined. (But then, of course, they would not be able to make political hay off it…) It makes complete sense to keep NYC under lockdown for a considerable while longer. It makes none at all to do the same for agriculture and food processing — which would add famine to the already staggering economic cost of the pandemic.

POSTSCRIPT: Meanwhile, the Washington Post, in a rare display of journalism, dropped a bombshell (archive copy at http://archive.is/Tg5oo in case it gets “airbrushed”)” It appears that my friend “masgramondou” was not far off the mark with his origin theory for the epidemic.

In January 2018, the U.S. Embassy in Beijing took the unusual step of repeatedly sending U.S. science diplomats to the Wuhan Institute of Virology (WIV), which had in 2015 become China’s first laboratory to achieve the highest level of international bioresearch safety (known as BSL-4). WIV issued a news release in English about the last of these visits, which occurred on March 27, 2018. The U.S. delegation was led by Jamison Fouss, the consul general in Wuhan, and Rick Switzer, the embassy’s counselor of environment, science, technology and health. Last week, WIV erased that statement from its website, though it remains archived on the Internet.

What the U.S. officials learned during their visits concerned them so much that they dispatched two diplomatic cables categorized as Sensitive But Unclassified back to Washington. The cables warned about safety and management weaknesses at the WIV lab and proposed more attention and help. The first cable, which I obtained, also warns that the lab’s work on bat coronaviruses and their potential human transmission represented a risk of a new SARS-like pandemic.

“During interactions with scientists at the WIV laboratory, they noted the new lab has a serious shortage of appropriately trained technicians and investigators needed to safely operate this high-containment laboratory,” states the Jan. 19, 2018, cable, which was drafted by two officials from the embassy’s environment, science and health sections who met with the WIV scientists. (The State Department declined to comment on this and other details of the story.)

The Chinese researchers at WIV were receiving assistance from the Galveston National Laboratory at the University of Texas Medical Branch and other U.S. organizations, but the Chinese requested additional help. The cables argued that the United States should give the Wuhan lab further support, mainly because its research on bat coronaviruses was important but also dangerous.

As the cable noted, the U.S. visitors met with Shi Zhengli, the head of the research project, who had been publishing studies related to bat coronaviruses for many years. In November 2017, just before the U.S. officials’ visit, Shi’s team had published research showing that horseshoe bats they had collected from a cave in Yunnan province were very likely from the same bat population that spawned the SARS coronavirus in 2003.

“Most importantly,” the cable states, “the researchers also showed that various SARS-like coronaviruses can interact with ACE2, the human receptor identified for SARS-coronavirus. This finding strongly suggests that SARS-like coronaviruses from bats can be transmitted to humans to cause SARS-like diseases. From a public health perspective, this makes the continued surveillance of SARS-like coronaviruses in bats and study of the animal-human interface critical to future emerging coronavirus outbreak prediction and prevention.”

The research was designed to prevent the next SARS-like pandemic by anticipating how it might emerge. But even in 2015, other scientists questioned whether Shi’s team was taking unnecessary risks. In October 2014, the U.S. government had imposed a moratorium on funding of any research that makes a virus more deadly or contagious, known as “gain-of-function” experiments.

[…]

There are similar concerns about the nearby Wuhan Center for Disease Control and Prevention lab, which operates at biosecurity level 2, a level significantly less secure than the level-4 standard claimed by the Wuhan Insititute of Virology lab, Xiao said. That’s important because the Chinese government still refuses to answer basic questions about the origin of the novel coronavirus while suppressing any attempts to examine whether either lab was involved.

[*] The reason for the historical name “Spanish Flu” is simple. There were outbreaks in army barracks across the front, but those were hushed up due to wartime censorship. Spain was neutral in WW I, so its press was the first to significantly report on the epidemic. The name “Spanish” has stuck until quite recently.

ADDENDUM: welcome Instapundit readers! Via your intrepid host linking a NYPost article, I found this recent study from MIT showing the major role the NYC subway had in spreading the infection. This is my face. It is shocked.

ADDENDUM 2: I linked an interview with South Korean COVID19 expert Dr. Woo-Joo Kim of Korea University Guro Hospital in an earlier update. Commenter “reactionary” on Instapundit drew my attention to the followup interview, which is highly recommended (remember, South Korea was one of the first countries to get the epidemic under control). He starts discussing cytokines and cytokine storm about 14 minutes into the video (in Korean with English subtitles).

6 thoughts on “COVID19, April 15, 2020 update: Cytokine storm — the immune system “killing the patient in order to save him/her”

  1. COVID19 expert Dr. Woo-Joo Kim
    That actually sounds like a villain’s name in some cartoon full of stereotypes.

    What’s amazing to me is how much of all this was previously laid out, but no one* saw it. The “cytokine storm” thing was something I read over a month ago. I found out about HCQ when I first read about the French study – where it was specifically mentioned that they tried it because it was already used for exactly this sort of thing – viruses causing pneumonia – as an “off label” use. Seems no one else read that bit.

    Why do we listen to the people promoted to “Expert” during ‘peacetime’ again? They’re inevitably hidebound, self-important ignoramuses.

    (* “No one” defined as the self-defined experts and our noble firefighters in the media. *I* saw it. I’m sure plenty of other nobodies saw it, too. But no one listens to us.)

  2. […] (4) Instapundit’s feed is full of examples of further protracted lockdown measures being openly defied even in Manhattan (!). He calls this “Irish democracy”. I believe, and continue to believe, that short and intense lockdowns work in densely populated countries like my own — but what is currently going on in some US states amounts to perpetual moving of goalposts, and increasingly looks like a flag of convenience for agendas unrelated to epidemiology. The “Irish democracy” response then sooner or later became inevitable. As I have pointed out earlier, the active cases graphs in European countries (+Israel) that have reopened have yet to show any signs of resurgence.(5) Finally, as a long-time admirer of Richard Fernandez’s work, I was rather amused to see him use the Cytokine Storm metaphor for blunt-instrument lockdowns that you might have seen here. […]

  3. […] What difference a year can make! From ‘bug-eyed right-wing conspiracy theory’ to mainstream. And yes, a lab leak during risky ‘gain of function’ research (thanks to shoddy biocontainment discipline at the Wuhan lab) is what I’ve been suspecting for the past 8-9 months, and what “masgramondou” was blogging about in early April last year. [To be fair to the WaPo, last April they  may have been the first mainstream media source  (archive copy at http://archive.is/Tg5oo ) to report on biosafety concerns at the Wuhan Level 4 biocontainment facility.] Quoting again what I reported then: […]

  4. […] You may recall that, right back to the beginning of the pandemic, some people were speculating that this was either an escaped bioweapon [very dubious] or the result of a lab leak during “gain of function” research. This was pooh-poohed all over as a conspiracy theory, but from the beginning there were mainstream media sources who questioned the CCP’s official narrative: as I reported on April 15 last year, […]

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