COVID19 update, June 8, 2020: timeline pushed back to October 2019?; leaked German Interior Ministry internal report; hydroxychloroquine prophylactic use study

Just a few quick updates today, as things were busy at work.

(1) The time line for the epidemic keeps getting pushed back further? According to an ABC exclusive report , satellite imagery of parking lots of Wuhan hospitals in October 2019, compared to the same month the previous year, indicate unusual levels of activity. Moreover, internet searches on Baidu at the time supposedly had a number of queries for flu/SARS like symptoms. I am not wholly convinced, but who knows?

 

(2) An internal German report from “Referat KM4” of the BMI (Federal Interior Ministry), that was strongly critical of the “overreaction” of the German government to the pandemic, was leaked to the press. A PDF of the full text is here: (accompanying provenance info): Powerline has a summary in English. A little googling turned up an organigram in which KM4 shows up as “Schutz kritischer Infrastrukturen” (protection of critical infrastructures), one of six Referate (idiomatically: desks, sub-departments) in the department Krisenmanagement und Bevolkungsschutz (Crisis Management and Population Protection).

The report argues that mortality is a small fraction of the annual all-cause mortality in Germany [of course, this argument is open to the “well, that is so because we took action quickly” argument], and indeed, worldwide excess mortality at the time of writing (May 11) was one-sixth of that during the 2017/8 seasonal flu epidemic.

I haven’t waded through the entire report, which is nearly 100 pages long, but it is preceded by a 2-page Kurzfassung (“short version”, idiomatically “Executive Summary”). Item 3 of the Executive Summary speaks of a “Fehlalarm” (false alarm) and laments:  

The fact that the suspected false alarm remained undetected for weeks has a major reason
that the existing framework for action of the crisis unit and the
crisis management in a pandemic do not include appropriate detection tools that
automatically trigger an alarm and initiate the immediate cancellation of measures
as soon as either a pandemic warning turned out to be a false alarm or
it is foreseeable that collateral damage — particularly in terms of destruction of human lives — threatens to become larger than the health consequences and especially the lethal potential of the disease under consideration.

The report explicitly distances itself from economic cost-benefit calculations and, in item 4, argues that collateral damage in lives is larger than the damage of the original epidemic. 

Probably the most inflammatory sentence of the executive summary is “One reproach [from the public] might be that, in the Corona crisis, the State has shown itself to be one of the greatest producers of fake news” (Ein Vorwurf könnte lauten: Der Staat hat sich in der Coronakrise als einer der größten fake-news-Produzenten erwiesen.)”

German governmental authorities have tried to dismiss this report as “one person’s opinion”, but — agree with the report or not — it seems to be a good deal more than that. 

(3) Dr. Seheult looks at another hydroxychloroquine clinical trial: this time it looks at a prophylactic regime.

https://doi.org/10.1056/NEJMoa2016638

A group of about 800 patients who reported high-risk contact (nearer than 6th for more than 10 minutes) with a known COVID-19 carrier was split into two arms. One arm was given a 5-day hydroxychloroquine (HOcq) regimen, the other a placebo. Interestingly, and noted by Dr. Seheult, again no zinc!

The percentage of people who developed COVID19 was somewhat lower in the HOcq arm (11.8%) than in the placebo arm (14.3%), but with this sample size, there is about one chance in three the difference is due to chance. (What he didn’t highlight is that, even with high-risk contacts, the risk of contagion is much lower than you might intuitively expect.) 

A fairly large proportion of test subjects in the HOcq arm reported gastrointestinal complaints, but interestingly, no severe adverse events were reported. (HOcq is known to lead to QT-prolongation: in combination with other drugs that do this, such as the macrolide antibiotic azithromycin, the cumulative effect may lead to heart arrhythmias.)

Anyway, let Dr. Seheult explain it himself:

 

(4) Dr. Mike Hansen discusses differences between autopsy reports of COVID19 deaths and deaths from seasonal flu

COVID19 update, May 30, 2020: Fang Fang’s “Wuhan Diary”

The Chinese novelist Fang Fang has lived most of her life in Wuhan, going back to the days before the Cultural Revolution. Until her retirement, she used to be the provincial chair of the Chinese Writers Association. 

(Wuhan, the capital of Hubei province, was originally three separate cities named Wuchang, Hankou and Hanyang, all lying on the confluence of the Han and Yangtze rivers.)

When it became clear that an epidemic was breaking out, she started writing diary entries and posting them  on Chinese social media. They quickly acquired a following in the millions, despite furious attempts of online censors to airbrush them away. By the time the lockdowns on Wuhan were lifted, the combined diary had reached book length.  

Now translations in both English and German have come out. I read the English translation, which is available on Amazon. The rating is dragged down by a number of 1-star reviews posted by obvious “50-Cent Army” troll reviewers. So I decided to read the book for myself.

I warmly recommend it, despite its high price ($19.99). It is a unique first-person document by an articulate person with lots of contacts, including in the medical system.

It seems that the Wuhan residents were just as bamboozled by the ChiCom regime as the West. Doctors at the Central Hospital apparently realized early on that they were not just dealing with a new SARS-like infection, but that it was contagious person-to-person. After attempted whistleblower  Dr. Li Wenliang was strong-armed by the police into confessing he had been spreading false news, the others apparently restricted themselves to quietly warning each other. Yet officials eventually realized something was up and organized a high-level meeting on the 14th, which ended inconclusively. Even the Chinese New Year celebration was allowed to proceed.

She tells numerous stories of friends, acquaintances, and relatives who succumbed to the disease — many of them surprisingly young. Many medical personnel (including Li Wenliang) were among the early casualties, but also such people as journalists and cameramen.

She also relates the harrowing period where the local medical system was overwhelmed and patients would die while waiting to be admitted. This was a brief situation, alleviated when medical personnel and supplies started flowing in from other parts of China. 

She highlights the inventiveness of the locals in coping with the lockdowns and the attendant logistical problems. For example, as trying to shop individually was problematic (you were allowed out of your apartment complex once every 3 days) and often stores could not handle the flood of calls, an informal association of residents would collect orders, place a centralized bulk order, then distribute the ordered grocery parcels, at first by placing them in the building’s courtyard, then by placing them in buckets lowered from the windows of residents.

Food donations from other parts of China were apparently abundant enough that distributing them before they spoiled became a problem. She proposed a surprisingly (or not) “capitalist” solution: deliver to grocery stores (who have the storage and the delivery network in place), and let them resell at highly discounted prices meant to cover their distribution costs. 

While she affirmed the necessity of a strict lockdown, she highlights a number of instances where unthinking and callous enforcement of the letter of regulations, with no room for common sense, led to suffering and deaths. (One example that stands out in my mind was a special-needs child left to fend for itself when its father was placed in isolation. Another was a married couple stuck on a bridge between two boroughs because the two spouses had residence permits for opposite banks of the river.) 

“People often have reasons that they use to describe their actions, such as “we were just carrying out written directives.” But reality is filled with all kinds of unpredictable changes, whereas written directives are often prepared hastily with only broad guidelines. Moreover, those written directives are mostly composed with common sense in mind, so they are usually not in direct contradiction with the basic principles of humanitarianism. All we need is for the people assigned to enforce these principles to have just a little more humanistic spirit; just enough so that a driver who had been stuck out on the highways for more than 20 days wouldn’t end up with his life in danger; just enough so that when someone is infected with coronavirus, a crowd of people doesn’t end up sealing their front door with a steel rod so that everyone is locked inside; just enough so that when an adult is forced into mandatory quarantine, their children don’t end up starving to death alone at home. That is all I am asking for.”

Some of her tales will sound familiar — for example, how the suspension of all non-emergency medical services at the height of the epidemic led to other medical problems being neglected (e.g., dialysis and chemotherapy cases). (Apparently she and two of her siblings are diabetic, and the siblings have additional chronic medical problems, so this is something they experienced first-hand. Her ex-husband caught COVID but survived.) 

She also described, via her medical contacts, that mortality at the hospitals decreased once the capacity crunch was over and the doctors had refined their treatment protocols. She mentions remdesivir being applied with some success: non-intubated patients were also often treated with traditional Chinese remedies alongside Western medicine. She herself took various herbal potions in an attempt to boost her immune system. 

Telling it like it is, warts and all, earned her enemies, and even death threats.

“Today there is something I want to get off my chest that has been weighing on me for a long time: Those ultra-leftists in China are responsible for causing irreparable harm to the nation and the people. All they want to do is return to the good old days of the Cultural Revolution and reverse all the Reform Era policies. Anyone with an opinion that differs from their own is regarded as their enemy. They behave like a pack of thugs, attacking anyone who fails to cooperate with them, launching wave after wave of attacks. They spray the world with their violent, hate-filled language and often resort to even more despicable tactics, so base that it almost defies understanding.”

In a footnote, she explains that by ultra-leftists she means ultra-Maoist nostalgics for the Cultural Revolution era, opposed to the reformist polices introduced by Deng Xiaoping.  These people report her posts on the Chinese Twitter-clone and managed to get her account blocked a number of times.

In this atmosphere, newspapers practice self-censorship. She highlights the story of a man who left a testament of 11 word, “I donate my body to the state… what about my wife?” where the newspaper would only highlight the first seven words as concern for his surviving spouse was apparently not worthy of sharing the limelight with his selfless devotion to the state.

(She does mention that autopsies of people like that man were invaluable in helping doctors understand what they were dealing with, notably the ARDS.)

The party leadership and officialdom — well, let me quote her:

“The world of officialdom is filled with people who have never learned a damn thing in their entire lives, but one thing they have mastered is the art of putting on a show; and they have ways to deal with you that you would have never imagined even existed. Their ability to shirk responsibility is also second to none; if they didn’t have a good foundation in all these worthless skills, this outbreak would have never grown into the large-scale calamity that it is today.”

She mentions that three groups of specialists had come to visit during the earlier stages of the outbreak. The first two had accepted the claim that no person-to-person transmission took place, but the leader of the 3rd group —  one Dr. Zhong Nanshan, who had earned his spurs in managing the original SARS outbreak — did not take no for an answer. Under insistent questioning, it was admitted that a patient had infected 14 others, and he announced on January 20 that person-to-person transmission did take place. By then, of course, precious time had been lost.

 

 

 

 

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).