COVID19 update, June 16, 2020: Blue-chip Oxford trial finds inexpensive steroid dexamethasone saves lives in severe COVID-19 cases; flare-ups in Israel and in China

(1) [Hat tip: Yves not-Cohen]: via De Standaard and the BBC, Oxford University reports a breakthrough in the management of severe COVID-19 cases: https://www.recoverytrial.net/files/recovery_dexamethasone_statement_160620_v2final.pdf

I have blogged earlier about anecdotal reports that steroids (for the group I was quoting, methylprednisolone) were being used in an attempt to hold “cytokine storm” at bay, and intuitively this makes a lot of sense. But now we have a large-scale clinical trial to back it up.

A total of 2104 patients were randomised to receive dexamethasone 6 mg once per day (either by mouth or by intravenous injection) for ten days and were compared with 4321 patients randomised to usual care alone. Among the patients who received usual care alone, 28-day mortality was highest in those who required ventilation (41%), intermediate in those patients who required oxygen only (25%), and lowest among those who did not require any respiratory intervention (13%). Dexamethasone reduced deaths by one-third in ventilated patients (rate ratio 0.65 [95% confidence interval 0.48 to 0.88]; p=0.0003) and by one fifth in other patients receiving oxygen only (0.80 [0.67 to 0.96]; p=0.0021). There was no benefit among those patients who did not require respiratory support (1.22 [0.86 to 1.75]; p=0.14). Based on these results, 1 death would be prevented by treatment of around 8 ventilated patients or around 25 patients requiring oxygen alone. Given the public health importance of these results, we are now working to publish the full details as soon as possible.

In plain English, p=0.0003 means there are three chances in ten thousand that the difference is due to coincidence , p=0.0021 that there are 2.1 chances in a thousand of this happening. That the steroid would have no benefit in patients who show no signs yet of “cytokine storm” makes perfect sense.

The study’s authors tout this as the first drug that actually saves lives. Indirectly, Remdesivir and other antivirals may do so if given early in the disease progression, by preventing escalation to cytokine storm: once you get there, you have missed the boat for antivirals and need to focus on stopping the patient’s immune system from killing him.

That dexamethasone is a dirt-cheap drug that has been in common use for decades is of course a nice bonus.

(2) Related, via The Epoch Times (an expat Chinese newspaper fiercely opposed to the regime) a report by the British Heart Foundation about TRV027, an experimental drug by Trevena that restores the angiotensin II vs. angiotensin 1-7 balance (which the virus disrupts through binding to ACE 2 receptors) and thus tries to prevent excessive blood clotting at the source.

Also related, US Senate testimony  by Pierre Kory MD of the COVID19 Critical Care Group.

 

(3) Israel, after a lull and after essentially fully reopening, is now seeing a flare-up of about 200 cases per day. In part this can be ascribed to more intensive testing efforts: past data indicate we had about 10 undocumented asymptomatic or mild cases for each documented case.  (Yesterday, 13,425 were tested, of which 196 found positive.)

The head of the research division of the Maccabi HMO (one of the four authorized Health Maintenance Organizations in Israel, and one of the “big three”) explains to The Times Of Israel that this time around, most of the cases are children or young people (which are less vulnerable), and that many of the children are asymptomatic.

 

In Tel Aviv, which is seeing the fastest spread of the virus, some 57 percent of Maccabi members who tested positive in June are aged 18 or under, Anat Ekka-Zohar told The Times of Israel. There is a similar pattern in other central Israeli cities where cases are growing, she said. In Peta[c]h Tikva the figure is 77%, in Jaffa 60% and in Bnei Brak 43%.

Lots of the current adult carriers are aged 45 or under, Ekka-Zohar said. Some 73% of Maccabi members nationally who tested positive in June are 45 or under, and in Tel Aviv, the figure is 79%.

Maccabi, which is responsible for the health of 2 million Israelis, says that just 1.3% of the people it found to be infected in June are aged 75 or older, Ekka-Zohar said.

Looking at the figure for the 65-plus age group, which is considered the most at-risk of serious illness or death if infected, Ekka-Zohar said it stands at 6.7% for June cases. In April, that age group accounted for around 12% of Maccabi’s cases, she added.

The fact that the most vulnerable aren’t being infected in large numbers bodes well, Ekka-Zohar said, commenting: “It’s not going to provoke a crisis in terms of the number of hospitalizations or in terms of ventilators.”

 

(H/t: Mrs. Arbel.) A somewhat PG-13 rated piece of local humor about masks: the caption says “wearing your mask like thisis like wearing your underpants like that. [And underneath] Please wear your mask correctly.”

Israeli mask humor

(4) “Nothing to see here, move along.” The regime is now blaming “European salmon” for a new coronavirus outbreak in Beijing?! Yeah right — if you believe that, I have some beachfront land in Arizona for sale. Most likely, this is just the 2nd wave of the epidemic they claimed they had under full control. Remember this piece of advice by a Hong Kong resident (warning: language alert).

COVID19 update, May 14, 2020: drug cocktails greater than the sum of their parts

(1) The term “drug cocktail” is best known from AIDS, where the introduction of “cocktails” of (usually three from at least two different classes) antiretrovirals helped turn HIV from a death sentence into a long-term manageable disease.
Now (h/t: Mrs. Arbel) a team from Hong Kong has achieved excellent results for COVID19 using a different cocktail, reports the Jerusalem Post. The full medical article in The Lancet can be read here: https://doi.org/10.1016/S0140-6736(20)31042-4

The cocktail in question has three components:

  • The HIV drug Kaletra, itself a mixture of two protease inhibitors, Lopinavir and Ritonavir.
  • The hepatitis drug Ribavirin, a nucleoside analog that can mimic both the letters A and G of the genetic code, and thus messes with copying of the viral RNA (cf. my earlier posts on Remdesivir)
  • The immunomodulator Interferon beta-1b, better known to multiple sclerosis patients as REBIF.

The control group was given just Kaletra. Otherwise, both groups received standard supportive care, including antibiotics for secondary bacterial infections.

What’s with the protease inhibitor? Many of these viruses (including SARS-NCoV-2 have their envelope etc. Proteins encoded as a single long “protein sausage” on their RNA. After protein synthesis in the ribosome (the cell organelle that assembles proteins from amino acids according to the ‘program tape’ on the RNA), a protease then splits the ‘sausage’ into individual ‘links’.

So we have two drugs that tamper with the ability of the virus to make its envelope, plus one that inserts junk ‘letters’ in the copied RNA. Even if each partially successful, they will slow down viral reproduction. So what is the role of the beta-interferon? To tell the body’s immune system: “don’t go berserk, take it easy!” and prevent cytokine storm.

If treatment was started less than 7 days after onset of symptoms, the “triple cocktail” group showed better clinical and virological outcomes than the control group across all meaningful measured variables. For the subgroups of patients where treatment was delayed longer, there was no statistically significant difference in outcomes between the cocktail and control group. So early intervention is worth a lot.

Median time to negative RT-PCR test was 7 days for the “cocktail” group, compared to 12 days for the control group.

It’s not a magic bullet drug: every doctor dreams of what Frederick Banting experiences when he first administered insulin to boys in diabetic coma, where the first boys were waking up before he’d finished injecting the last. But that kind of spectacular success is the rare exception in drug research.

What we can safely say we have here, I believe, is a ‘cocktail’ that is greater than the sum of the parts. And a nice thing about cocktails of existing drugs: each component already has undergone clinical trials and obtained FDA (or foreign equivalent) approval individually.

What about side-effects? Reading Table 4 in the paper, the difference with the control group for nausea, diarrhea,… is not statistically significant. No patients in the ‘cocktail’ group suffered severe adverse events, vs. one in the ‘Kaletra only’ control group.

(2) My friend “masgramondou” weighs in on the source code of the “Ferguson Model”: All models are wrong, and some are useless. Or worse than useless, in this case. He points to another model that might at least be somewhat more transparent than the others: https://covid19-scenarios.org, developed by the group of Prof. Richard Neher at U. of Basel, Switzerland.

COVID19 update, May 11, 2020: hydroxychloroquine bummer; breakthrough in understanding of the severe disease

Two major updates today, one a bummer, one confirmation of an insight at the cellular level.

(1) The first large-scale clinical trial with hydroxychloroquine, at NY Presbyterian, was just published in the New England Journal of Medicine. http://www.nejm.org/doi/10.1056/NEJMoa2012410 Dr. John Campbell comments at length on YouTube, and as is his wont, strenuously avoids politicking. https://www.youtube.com/watch?v=1XCP1WzOY6M

Watch the whole video. But in a nutshell: there is no statistically significant difference in outcomes between the hydroxychloroquine and control arms of the study. This is a major bummer, as many medical professionals (and not just President Trump) had high hopes based on initial positive reports and several plausible mechanisms.

As Dr. Campbell says, it sounded plausible enough at the time they were desperate for something, anything they could repurpose. Especially given the known immunomodulatory effects (cf. use in arthritis, lupus) and as it became increasingly clear people were getting killed by their own immune systems going amok rather than directly by the virus. Besides, it worked in the test tube against the old SARS.

More’s the pity, since it was something they could use off the shelf and didn’t cost an arm and a leg. So far, Remdesivir is the only thing that’s passed the double-blind test [it got FDA approval right after]— and that’s (a) only an incremental therapeutic benefit, no magic bullet; (b) a proprietary drug that Gilead themselves will have to license to other companies because they simply can’t manufacture enough. (Hoffmann-LaRoche probably can.)

(2) Now for the major insight (hat tip: Mrs. Arbel). Haaretz English Edition [*] has a write-up in popular language (archived copy here http://archive.is/g6qaL ) of a paper from the Weizmann Institute that just came out in the prestigious journal CELL. https://doi.org/10.1016/j.cell.2020.05.006

This paper helps rationalize at the level of single cells what has become increasingly clear on an empirical, “macro” level: that COVID19 is really two diseases in one. The first stage is a unpleasant but not life-threatening viral disease — and about 80% of patients on average (fewer for older patients, but over 95% of young patients) just get better on their own, and that’s the end of it. The remainder, who proceed to the second stage, get a massive immune overreaction (“cytokine storm”, CS) that becomes life-threatening (and kills a nontrivial percentage of patients). I have linked the videos by Drs. Hansen and Seheult (both pulmonologists) about the clinical picture in previous updates; postmortem, several German and Swiss pathologists have shared the results of many autopsies. , where severe blood clotting secondary to CS was seen over and over, causing organ failures and strokes as well as ultimately death by heart attack or pulmonary embolism.
Now a paper from the Weizmann Institute, by the team of Prof. Ido Amit at the Department of Immunology, offers a glimpse at what goes on at the cellular level.

In the study, which [also involved] research assistants Amir Giladi and Pierre Bost, researchers used state-of-the-art genomic technologies which included a method known as single-cell genomics, an area developed and led by Prof. Amit. […] By obtaining a picture of the cell at a given moment, one can compare the differences between the activity of cells invaded by the coronavirus in severely and lightly affected individuals. Researchers can see which cells and genes are activated and which cells are silenced, thus learning about changes in inter-cellular communication and about cells that are activated by the virus in areas where it is active.

The key question of what differentiates biological processes and the actions of the immune system in severely ill COVID-19 patients as opposed to those who are slightly ill has been occupying researchers and physicians since the virus was first detected.
In the lungs of seriously ill patients, [Amit and coworkers] found that macrophages – cells that normally assist in ridding the lungs of infection, viruses and microbes – are replaced by cells that exacerbate the illness. The researchers also found that in seriously ill patients, the coronavirus neutralizes the immune system’s T-cells, which also fight infections, thereby allowing other viruses that are present in the body to inflict their damage. […] The researchers behind the study hope that a deeper understanding of the factors leading to a patient’s deterioration will help find weak spots in the chain of reactions initiated by the virus in severe cases, paving the way for effective treatments that would prevent or significantly curtail the impact of the disease.

The pattern of the disease among people who are hit hard is quite clear: After a week of mild symptoms, there is a rapid and sharp deterioration in their condition, characterized by hyperactivity of the immune system called a cytokine storm. This hyperactivity leads to serious damage to a patient’s health, often leading to a collapse of multiple systems, including the heart, liver and kidneys. In the lungs, the disease is characterized by damage to macrophage cells, whose role is to clear the lungs of infections.

The study analyzed hundreds of thousands of cells that were taken from the lung fluid of seriously ill patients, slightly ill patients and healthy people. The researchers discovered which types of cells are invaded by the virus and learned about its pathway. They found that the virus usually attacks epithelial cells, which in the lungs are responsible for respiration by enabling transport of oxygen from the air to the blood. “Due to the infection, the whole immune environment of the lungs undergoes a total transformation” explains Amit.

The study showed that in patients who are severely hit by the virus, there is a dramatic effect on the immune system as compared to patients who are only slightly affected. In the former, macrophages in the lung tissue are replaced by other immune system cells. “We found that they are replaced by monocytes, blood cells which accelerate a cytokine storm. They are recruited from the circulation as part of the overreaction of the immune system,” explains Amit.

The researchers found an enhanced presence of polypeptide cytokines called IL-6 and IL-8 in seriously ill patients. These cytokines are usually released by the monocytes, serving to either augment or suppress inflammation according to need. In this case, they facilitate inflammation. “The cytokine storm produced by the virus prevents the immune system in these patients from launching adaptive processes which are required for mounting an appropriate immune response,” says Amit. “In other studies we’re involved in, together with researchers from China and Italy, we see enhanced cytokine levels in the blood of severely ill patients before any pathological signs are evident.”

Another change that accompanies the cytokine storm involves the activity of T-cells. “In contrast to patients with light symptoms, seriously ill patients have T-cells that are neutralized and inactive,” says Amit. The researchers found that this dramatic change causes indirect damage, such as infection by other viruses which the immune system had previously managed to repulse.

I’d been wondering for a while for how many people who died of COVID19, secondary opportunistic infections (by viruses or drug-resistant “hospital bacteria”) were the proximate cause of death, or a contributory one, even if the root cause was still COVID19.

The researchers are now developing clinical studies that will use treatments to protect macrophages, with the hope that they will be able to prevent a deterioration in patients who are mildly impacted by the virus.

More than that: this may give another impetus to treatments that combine immunomodulators with anticoagulants (to combat the severe thromboses that appear to be a common by-product of the severe disease).

COVID19 update, April 22, 2020: the two faces of the disease, as explained by a pulmonologist; IL-6 and estrogen explaining gender differences?

(1) I saw a video by pulmonologist Mike Hansen MD that made me go “aha!”. He may be pitching its message a bit too strongly, but was delivered in a highly entertaining manner, and is easy to follow if you have some basic medical knowledge. See the video here. (Something is broken with the YouTube embedding widget that makes WordPress glacially slow to edit on my computer.)

It is almost like the disease has two faces. In the vast majority of patients, there is no involvement of the lower respiratory tract — just upper respiratory and some gastro-intestinal involvement (there are ACE2 receptors there), rarely some cerebral. This disease picture is the (generally) nonlethal one, ranging in severity from mild cold to severe flu without secondary infection. Such patients will get better on their own with nothing more than standard supportive treatment, like you would for a nasty flu at home.

It’s when the infection goes down to the lower part of your lungs that all hell can break loose. Effectively, the inflammation of the alveoli sets off a chain reaction (which he explains in great detail) that can easily blow up into ARDS (acute respiratory distress syndrome) and cytokine storm, and ends up with the patient getting killed by his own immune system. The key is to intervene before this happens.

In his picture, antiviral drugs would be most useful in the early stages — to stop the infection from spreading to the lower lungs — or even for prophylaxis. (However, I’d point out that, especially with remdesivir, there have been “saves” of severely ill patients.) In later stages of the disease, immunosuppressants actually would be more valuable, to rein in the immune system running amok.

The people who say “it’s just a flu” are actually right in 90+% of symptomatic cases. In the remainder it’s almost like what my brother would call the “autoimmune disease from Hell”.

Two other nuggets from the video:

(2) John Campbell keeps coming back to vitamin D and its vital role in the immune system. He points out that, while only 14% of Britons are nonwhite, they constitute nearly one-third of critical COVID19 cases. Socio-economic and cultural factors (e.g., multigenerational families under one roof, like is common in Italy) aside, vitamin D deficiency is much more common at northern latitudes if you have a dark skin type. (Anecdotally, I know that a family acquaintance of Yemenite-Jewish heritage [and hence with very dark skin] who moved to Sweden suffered all sorts of health problems, until UV lamps and vitamin D supplements entered the picture.[*] ) This aspect of the problem is very easy to solve…

Dr. Campbell is a bit dismissive of the estrogen-IL6 hypothesis “since why would there then be a gender difference at post-menopausal age?” Instead, he points out that many immunity-related genes are on the X chromosome, and if you have one defective copy and you’re male, that’s your only copy, while a female would have the 2nd X chromosome… (This is aside from the risk factor of smoking — in countries like China much more prevalent in men than in women.)

In another video (h/t Mrs. Arbel), he backtracks on earlier comments about Greece, and notes they have been more proactive than he thought (canceling school 9 days before the UK, in fact) and are now seeing the fruits thereof, as cases have dwindled. A similar decrease in deaths will lag by several weeks.

(3) Chemical and Engineering News, the house organ of the American Chemical Society, looks at the challenges for Gilead Sciences in scaling up production of remdesivir to the millions of doses range. In the earlier case of Tamiflu, Hoffmann-LaRoche licensed manufacturing from Gilead Sciences — and was able to provide 200 million courses’ worth of Tamiflu in comparatively short order.

(4) Via Instapundit: is there a correlation between universal BCG (Calmette-Guérin) tuberculosis vaccination policy and reduced COVID19 mortality?

(See also https://www.medrxiv.org/content/10.1101/2020.03.24.20042937v1)

I found this database of global BCG policies www.bcgatlas.org (documented here). Let me show a map:

A (ochre) refers to countries with mandatory BCG vaccination, B (purple) to countries who had it as mandatory in the past, and C (orange-red) to countries where it was never mandatory. The blatant difference in mortality between (culturally and ethnically very similar) Portugal and Spain has been ascribed to me by a Portuguese US immigrant to the existence of a parallel private medical system “that actually functions”, unlike the government-only option in Spain; but I wonder whether BCG couldn’t play a role. (TB used to be endemic in Portugal.) Belgium vs. Germany (again, ethnically and culturally quite similar) is another case. However, what about France then?

Israel used to have mandatory BCG until 1982—which implies the older generation (the most at-risk) would see some benefits. (As vaccines go, BCG is a pretty blunt instrument that “trains” the first responders of the immune system, which are not terribly selective.) And indeed, in combination with our young-ish population pyramid and our warm climate (today the mercury hit 90°F), this may go some way towards explaining the comparatively low mortality in Israel.

(5) The NYT has (in part with political ulterior motives) been cheerleading extended lockdowns, so I was surprised to see this article there on the collateral damage of shutting down all “non-emergency” activity at hospitals while bracing for a COVID19 flood. (Archived copy here.)

[…] Early on, as the epidemic loomed, many hospitals took the common-sense step of halting elective surgery. Knee replacements, face lifts and most hernias could wait. So could checkups and routine mammograms.

But some conditions fall into a gray zone of medical risk. While they may not be emergencies, many of these illnesses could become life threatening, or if not quickly treated, leave the patient with permanent disability. Doctors and patients alike are confronted with a worrisome future: How long is too long to postpone medical care or treatment?

Delaying treatment is especially disturbing for people with cancer, in no small part because it seems to contradict years of public health messages urging everyone to find the disease early and treat it as soon as possible. Doctors say they are trying to provide only the most urgently needed cancer care in clinics or hospitals, not just to conserve resources but also to protect cancer patients, who have high odds of becoming severely ill if they contract the coronavirus.

Nearly one in four cancer patients reported delays in their care because of the pandemic, including access to in-person appointments, imaging, surgery and other services, according to a recent survey by the American Cancer Society’s Cancer Action Network.

Tzvia Bader, who leads the company TrialJectory, which helps cancer patients find clinical trials, said frightened patients had been calling to ask her advice about postponements in their treatment.

One woman had undergone surgery for melanoma that had spread to her liver, and was due to begin immunotherapy, but was told it would be delayed for an unknown length of time.

“She says, ‘What’s going to happen to me?’” Ms. Bader said. “This is not improving her chances.”

And some clinical trials, where cancer patients can receive innovative therapies, have been suspended.

“The mortality of cancer has been declining over the last few years, and I’m so terrified we are going backwards,” Ms. Bader said.






[*] As for me, I can’t be outside for more than 30 minutes or so on an Israeli summer day without nasty sunburn 😉 There is a reason the term “redneck” exists in the American South, as does “rooinek” in Afrikaans…

COVID19 update, April 21, 2020: Colchicine; more on COVID19-related pneumonia and “stealth hypoxia”; community testing in Los Angeles; Belgium as seen from Germany

(1) Via Mrs. Arbel, here is info on a clinical trial of the ancient-as-dirt drug colchicine. This has been in use since Antiquity for the treatment of gout (full disclosure: I have been taking it for a while, when a low-carb, high-protein diet intended to lose weight gave me a painful bout of this “rich man’s disease”): this clinical trial investigates whether its early administration to COVID19 patients may prevent “cytokine storm”. (More here at Physician’s Weekly) https://www.physiciansweekly.com/anti-inflammatory-drug-colchicine-on-deck-for-covid-19/

I am wondering more than ever whether the vast majority of dead from COVID19 aren’t killed by the patients’ own immune systems going amok. (This was what caused most deaths during the 1918 “Spanish” Flu: the main difference with the present epidemic — other than the causative agent which was an influenza virus then, a coronavirus now — is that in COVID19 the severe disease picture seems to be the exception rather than the rule, statistically speaking.

How rare? Consider Israel, which tests reasonably broadly and is conservative about diagnoses, albeit admittedly has a “younger” population pyramid than most Western countries. The screenshot below is from the daily report by its Ministry of Health: https://govextra.gov.il/ministry-of-health/corona/corona-virus/  

As of the time of writing, we have 13,883 verified cases (read: people testing positive for the virus): 9,072 of them in mild condition, 135 in moderate condition, just 142 in severe condition of which 113 on respirators, 181 deceased (of course, 181 too many), and 4,353 verified recoveries — defined here as previously diagnosed, now without symptoms and testing negative for the virus. (The “170” at the top of the graph are new cases added.) Moderate+severe+dead together is 4% (four percent) of the total infected. (Probably closer to 8% or 10% of symptomatic/overt cases — since anecdotally, it seems that about half of Israel’s verified “cases” [read: verified infections] are completely asymptomatic.)

(2) “masgramondou” Emailed me this one from the NYT (original link: https://www.nytimes.com/2020/04/20/opinion/coronavirus-testing-pneumonia.html?action=click&module=Opinion&pgtype=Homepage archived here http://archive.is/QSBfc) in which an emergency physician named Richard Levitan MD at Bellevue Hospital in NYC talks about “stealth hypoxia” in COVID19 patients. Unlike the usual fodder at the NYT, this is a factual report with no obvious political axe to grind. Some moneygrafs:

And here is what really surprised us: These patients did not report any sensation of breathing problems, even though their chest X-rays showed diffuse pneumonia and their oxygen was below normal. How could this be?

We are just beginning to recognize that Covid pneumonia initially causes a form of oxygen deprivation we call “silent hypoxia” — “silent” because of its insidious, hard-to-detect nature.

Pneumonia is an infection of the lungs in which the air sacs fill with fluid or pus. Normally, patients develop chest discomfort, pain with breathing and other breathing problems. But when Covid pneumonia first strikes, patients don’t feel short of breath, even as their oxygen levels fall. And by the time they do, they have alarmingly low oxygen levels and moderate-to-severe pneumonia (as seen on chest X-rays). Normal oxygen saturation for most persons at sea level is 94 percent to 100 percent; Covid pneumonia patients I saw had oxygen saturations as low as 50 percent.

[…]

A vast majority of Covid pneumonia patients I met had remarkably low oxygen saturations at triage — seemingly incompatible with life — but they were using their cellphones as we put them on monitors. Although breathing fast, they had relatively minimal apparent distress, despite dangerously low oxygen levels and terrible pneumonia on chest X-rays.

We are only just beginning to understand why this is so. The coronavirus attacks lung cells that make surfactant. This substance helps keep the air sacs in the lungs stay open between breaths and is critical to normal lung function. As the inflammation from Covid pneumonia starts, it causes the air sacs to collapse, and oxygen levels fall. Yet the lungs initially remain “compliant,” not yet stiff or heavy with fluid. This means patients can still expel carbon dioxide — and without a buildup of carbon dioxide, patients do not feel short of breath.

Patients compensate for the low oxygen in their blood by breathing faster and deeper — and this happens without their realizing it. This silent hypoxia, and the patient’s physiological response to it, causes even more inflammation and more air sacs to collapse, and the pneumonia worsens until their oxygen levels plummet. In effect, the patient is injuring their own lungs by breathing harder and harder. Twenty percent of Covid pneumonia patients then go on to a second and deadlier phase of lung injury. Fluid builds up and the lungs become stiff, carbon dioxide rises, and patients develop acute respiratory failure.

By the time patients have noticeable trouble breathing and present to the hospital with dangerously low oxygen levels, many will ultimately require a ventilator.

Silent hypoxia progressing rapidly to respiratory failure explains cases of Covid-19 patients dying suddenly after not feeling short of breath. (It appears that most Covid-19 patients experience relatively mild symptoms and get over the illness in a week or two without treatment.)

And then the best part!

There is a way we could identify more patients who have Covid pneumonia sooner and treat them more effectively — and it would not require waiting for a coronavirus test at a hospital or doctor’s office. It requires detecting silent hypoxia early through a common medical device that can be purchased without a prescription at most pharmacies: a pulse oximeter.

Pulse oximetry is no more complicated than using a thermometer. These small devices turn on with one button and are placed on a fingertip. In a few seconds, two numbers are displayed: oxygen saturation and pulse rate. Pulse oximeters are extremely reliable in detecting oxygenation problems and elevated heart rates.

Pulse oximeters helped save the lives of two emergency physicians I know, alerting them early on to the need for treatment. When they noticed their oxygen levels declining, both went to the hospital and recovered (though one waited longer and required more treatment). Detection of hypoxia, early treatment and close monitoring apparently also worked for Boris Johnson, the British prime minister.

Widespread pulse oximetry screening for Covid pneumonia — whether people check themselves on home devices or go to clinics or doctors’ offices — could provide an early warning system for the kinds of breathing problems associated with Covid pneumonia.

Read the whole thing.

(3) (via Instapundit) KTLA reports on a new community antibody study in Los Angeles County https://ktla.com/news/local-news/l-a-county-officials-to-provide-latest-update-on-coronavirus-crisis/?fbclid=IwAR3ItNdY_00D6FkDjQRn-x5rK71A2XqLg-xgvPQFSN0YfI9batMXXNA6-s0  which corroborates various earlier reports that the USA, at least, may have a very significant Dunkelziffer/“stealth infection rate”.

While Los Angeles County has reported a total of 13,816 coronavirus cases, early results from an antibody study conducted with the University of Southern California shows that hundreds of thousands more could have had COVID-19 in the past, officials announced Monday.

So far, 863 L.A. County residents have been tested between April 10 and 14 as part of the study.

The study estimates a prevalence of COVID-19 antibodies in the county to be 4.1%, with a range that could be as low as 2.8% and as high as 5.6%, when you factor in the reliability of the tests.

An estimated 221,000 adults to 442,000 adults at the high end may have been infected at some point before April 9 with COVID-19, suggesting that the number of total people in the county with a past or current infection is 28 to 55 times higher than the number of reported positive cases, Dr. Barbara Ferrer, L.A. County’s public health director said Monday.

[…]

Although the sample size was relatively small, Ferrer shared some early estimates about who was most likely to be infected:

Men were more likely than women to be infected. The estimated prevalence is 6% among men and 2% among women

7% of African Americans, 6% of whites, 4.2% of Asians and 2.5% of people who were Latinx who were tested were found to be positive for COVID-19

2.4% of people who were between the ages of 18-34 were positive

5.6% were between 35 and 54

4.3% who were 55 and older tested positive

(4) And in what is rather distressing reading, Die Welt (in German) wonders why neighboring Belgium (!) has the highest pro capita COVID19 mortality in the world — actually, the absolute numbers are larger than Germany’s, which has seven times the population of Belgium! Summarizing a few of their points:

(a) Belgium counts deaths “with” COVID19 as COVID19 deaths, in the name of “transparency”, even if the cause of death is different. Germany uses a  more restrictive definition.

(b) 50-70% of all deaths in Belgium are in homes for the elderly [about 20% of care home residents over 85 test positive in facilities where everybody was tested]. Die Welt cites a report in Belgium’s largest French-language daily, LE SOIR  Wie die Tageszeitung „Le Soir“ berichtet]  Staff went around without even face masks for weeks because of (c)

(c) there is an acute shortage of PPE, particularly masks. The emergency stockpile (from SARS days) had been destroyed pre-epidemic as it had passed the expiration date — and had not been replenished even though that could then easily have been done. (Now Belgium was forced to startup domestic production. [Becoming dependent on China is a recipe for disaster across the world.])

(d) Nevertheless, it’s not all doom and gloom. Spread in the general population has been contained, the number of cases grows more slowly, and the number of deaths has peaked and is now holding at about 300/day. But this is cold comfort, or as you say in both Dutch and German, “meager comfort”…

(e) Finally, as things are again picking up at my day job, I am grateful to the people who have started sending me article tips! 

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).

COVID19 update, April 12, 2020: Easter edition

Happy Easter to my Christian readers. Below are a few COVID19 updates.

(1) Dr. Seheult from MedCram, who is actually a pulmonologist himself, weighs in on the “to ventilator or not to ventilator” debate in Episode 53 of his COVID19 video series. He references a paper by an Italian team that distinguishes two “phenotypes” of clinical presentations in severe COVID19 patients: about 20-30% are “type H” who fit the classic criteria of ARDS and can benefit from intubation, while the remainder are “type L” who are best managed with noninvasive techniques.

Dr. Seheult also cites a “white paper” on COVID19 case management by a colleague. Most interesting for some of us, perhaps, are the prophylaxis recommendations:

  • Vitamin C 500 mg BID [=twice a day] and Quercetin 250-500 mg BID
  • Zinc 75-100 mg/day (acetate, gluconate or picolinate). Zinc lozenges are preferred. After 1-2months, reduce the dose to 30-50 mg/day. [Full disclosure: I started doing this two weeks ago. Especially people on vegetarian diets, who often have zinc insufficiencies, should take supplements. Zinc plays an essential role in hundreds of processes in the body, including the immune system. If you exclude iron in hemoglobin, zinc is actually the most common transition metal in the human body.]
  • Melatonin (slow release): Begin with 0.3mg and increase as tolerated to 1-2 mg at night [this appears to be primarily to ensure adequate sleep, which affects immunity]
  • Vitamin D3 1000-4000 u/day (optimal dose unknown). Likely that those with baseline low 25-OH vitamin D levels and those living [north of the 40th Parallel] will benefit the most.

(2) An article in the Israeli business paper GLOBES looks at the “underworld” of medical equipment procurement. (H/t: Mrs. Arbel)

(3) Immunosuppressant drugs in COVID19? Erik Wingren brings this case in Washington State to my attention: https://komonews.com/news/coronavirus/experimental-drug-helped-critically-ill-emergency-room-doctor-recover-from-covid-19 The drug administered here is https://en.wikipedia.org/wiki/Tocilizumab, which was actually FDA-approved in 2017for the management of cytokine release syndrome, (“cytokine storm”) as a side effect of CAR-T cell immunotherapies. It is increasingly becoming clear that, while most younger patients weather the disease well if they are symptomatic at all, a small subgroup appears to be predisposed to cytokine storm — in plain English, a massive overreaction of the immune system that does more harm to the body than the disease itself. In such situations (only!), immunossuppressants may actually save lives. (Cytokine storm appears to have accounted for the majority of deaths in the 1918 “Spanish Flu” pandemic — which explains why young and otherwise healthy patients were often more at risk than ) For more on cytokine storm in influenza more broadly, see this paper and that paper.

(4) A fairly large-scale (440 patients) clinical trial is in progress at the Erasmus Hospital in Rotterdam, the Netherlands with plasma antibodies from healed patients. (This is technically known as “passive vaccination”.)

(5) No, it’s not just Trump: in an op-ed in the German center-right daily DIE WELT, entitled “Diese WHO gefährdet ons” (This WHO endangers us) a human rights activist blasts the WHO, its leadership, and its execrable behavior in the early part of the crisis. As she puts it, the current WHO chair knows he owes his job to Chinese support and has been a devoted piper playing the tune called by his meal ticket.

But what’s more, DIE WELT reports in its lead article that the German domestic intelligence & counterespionage service, the Verfassungsschütz (Constitution Protection ) registers intensive influence and recruitment operations of German civil servants and elected officials by the Chinese regime. The goal is to get them to parrot the Chinese propaganda line that the country is a leader in combating the outbreak and helping the whole world do so, and that the virus did not come from China. “Together, let’s write a fairy tale,” (Wir schreiben gemeinsam ein Märchen) Die Welt comments sarcastically

UPDATE 1: Denmark is reopening in stages starting Wednesday April 15. In the first step, kindergartens and primary schools will be reopened, as their charges are least at risk from the consequences of an infection. The country has seen hospital occupancy drop since the beginning of the month.

In Austria some shops reopen this Tuesday, followed by other stores, restaurants and hotels in May.
Children go back to Norway’s kindergartens on 20 April and junior schools a week later.
In Bulgaria farmers’ markets are reopening. In the Czech Republic, shops selling building materials and bikes are back in business and rules have been relaxed for open-air recreation areas.
Spain, which along with Italy has been hardest hit by Covid-19, aims to allow non-essential workers back to work from Monday and will hand out protective masks at stations.