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Does recovering from Covid 19 cause immunity to new infection by Sars Cov2 ?

The WHO warns that it is not proven that we acquire immunity to Sars Cov2. If we don’t we are pretty much doomed. However, I don’t see how people could recover without developing immunity or develope immunity without memory with human immune systems. Here, as often, the burden of proof is placed on the optimistic hypothesis. Here again (third time) I dare to be optimistic (third time’s a charm).

At Daily Kos Mark Sumner has an excellent post on the topic. I cut and pasted my comment below. I agree with everything he wrote except the part about the common cold (which is a syndrome caused by one of dozens or hundreds of diffferent known viruses). In particular a key open question is whether all people who recover are immune but some are more immune than others (as he notes it is known that some have low anti Sars Cov2 antibody levels). Also it isn’t known if and when there will be new strains which evade the currently existing neutralizing antibodies.

His post is brief and too good to excerpt. Just click this link (then come back to read my post or not — it’s not at the same level)

First there is strong evidence that exposure to Covid causes people to make neutralizing antibodies, you mention this.  Here is my first google hit  .  In that article, the cell making such an antibody was immortalized by fusion with a leukemic cell and so there is a neutralizing monoclonal which can, in principal, be mass produced and used as a treatment.   The problem (as usual) is that it isn’t proven that it works and such proof takes a lot of time and money.

I don’t think there are viruses which infect us again and again.  We are infected by new viruses (here I include mutants of the old virus as in seasonal flu). The common cold is a syndrome not a virus. There are dozens to hundreds of known viruses which cause colds (with similar symptoms).  By your definition we get many different viral diseases with similar symptoms.

There is certainly a risk that Sars Cov2 will mutate in a way such that it is no longer neutralized by currently neutralizing antibodies,   and so there will be a new epidemic even if enough people are vaccinated to provide herd immunity to Sars Cov2 1.0 (influenza does this which is why there is seasonal flu).  It is also possible that this won’t happen (there wasn’t a smallpox 2.0 which infected people who were vaccinated).

Importantly, antisera against Sars Cov2 can be tested (in cell culture) against isolates from different continents.  So far, I think, the evidence is that sera (polyclonal) antibodies which block one strain block all existing strains (which sure doesn’t mean all strains which will ever exist).  There is a vaccine (good old fashioned killed virus vaccine, which has protected Rhesus macaques from infection by Sars Cov2 squirted in their lungs b
If our immune system can’t stop Sars Cov2, then how to people recover ? Why has anyone gone from positive to negative ?

Again, we don’t get the same common cold virus again and again.  There are many different cold viruses.  Most are picornaviruses (double stranded circular RNA genome, small, like polio) some are coronaviruses, and some are adenoviruses (which cause fierce colds).

I think the WHO is putting the burden of proof on the hypothesis that, whatever happens in us to beat one Sars Cov2 infection lasts for a while.  If this were not true, it would be unique (I think).

update: there is now more direct evidence in a non peer reviewed preprint here

Neutralizing antibody responses to SARS-CoV-2 in a COVID-19 recovered patient cohort and their implications
Fan Wu, Aojie Wang, Mei Liu, Qimin Wang, Jun Chen, Shuai Xia, Yun Ling, Yuling Zhang, Jingna Xun, Lu Lu, Shibo Jiang, Hongzhou Lu, Yumei Wen, Jinghe Huang

“neutralizing antibodies (NAbs)”

Plasma collected from 175 COVID-19 recovered patients with mild symptoms were screened using a safe and sensitive pseudotyped-lentiviral-vector-based neutralization assay. [skip]
SARS-CoV-2-specific NAbs were detected in patients from day 10-15 after the onset of the disease and remained thereafter. [skip]
Notably, among these patients, there were ten patients whose NAb titers were under the detectable level of our assay (ID50: < 40)

So according to We et al 165 out of 175 people had produced antibodies which prevent infection of cells. So this is evidence that people recover because of acquired immunity. On the other hand, not all subjects had measurable quantities of the antibodies (and the measure is what dilution blocks virus entry). So an exposed and immune passport would be unreliable — those 10 people are assessed as still vulnerable. This isn’t the end of humanity (165/175 is enough for herd immunity to get R under 1). But it matters for policy (as WHO insisted). Also “remained thereafter” doesn’t mean forever. It can only mean up until now which is, at most, months after the recovery (even if the blood was collected as soon as some people had recovered).

Good news.

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Remdesivir 6

Bad news from China. There was not a statistically significant benefit for patients with severe Covid 19 in the large Chinese controlled trial of Remdesivir for patients with severe Covid 19. The death rate was actually a tiny bit higher in the treated group.

New data on Gilead’s remdesivir, released by accident, show no benefit for coronavirus patients. Company still sees reason for hope

As a long time Remdesivirenthusast, I feel I have to note this result here. Now I will go off and cry.

OK also be stubborn. One argument is that the treatment was given too late when autoimmunity not viral replication was the main problem. A counterargument is that the trial of treatemnt for patients with moderate Covid was suspended and one suspects not with promising data.

Another argument is that the better end of the 95% confidence interval of the estimate of the relative hazard of improvement (mostly needed less extreme oxygen therapy) is 1.75 which is high. Part of the dismay is due to the error of considering failure to reject evidence in facor of the null. Priors should be updated with the likelihood and roughly in the direction of the point estimate. Here, as usual, there is a problem with treating current regulations as the scientific method. This is not as bad as looking only at the most pleasing part of a 95% interval, as I just did. I couldn’t resist.

On the other hand note the (slightly statistically insignificantly) worse death rate for the treated group.

But all in all a horrible disappointment (there were warning signs including the premature end of the trial)

Gilead, of course, contests the Statnews interpretation. They note that due to trouble recruiting patients the power of the test was low (my point above). They note there was (statistically insignificant) evidence that it helped. Needless to sau, they are even more biased than I am.

https://edition.cnn.com/2020/04/23/health/remdesivir-trial-gilead-premature/index.html

update: Again someone who might be biasd pro remdesivir, but definitely interesting.

Frederick Hayden, an infectious disease expert at the University of Virginia School of Medicine who helped the Chinese doctors conduct the study, disputed the characterisation that the study had failed.

“That is not correct,” Hayden said in an interview, when asked whether the results showed remdesivir had flopped. “My interpretation of them is not consistent with that headline.”

[skip]

Hayden said there was a mistake in the original manuscript and that it had since been revised. He said that the study was under review at a journal, which he would not identify. and that the authors were still waiting for page proofs. He declined further comment or elaborate until the study was published.

I want to believe that the mistake was saying that Remdesivir didn’t show ntiviral activity based in RT PCR

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Covid 19 Shutdown Politics

Advocates of quickly ending the shutdowns are in the news. Mostly, because one of them is President. Like most Americans, I think reopening soon would be a mistake (and remember I am in Italy where the shut down is severe compared to any State in the USA). I’m just going to assume that reopening by May 1 is a bad idea and try to understand who advocates it and why they do.

First the vast majority of Americans do not support reopening soon. There was the poll with 81% suppoert for a national lockdown. Also here is a poll which shows 10% believe gatherings of 10 or more will be safe by May 1. Interestingly the article reporting the poll is illustrated with a photo of an anti-lockdown demonstration. The silent majority is not photogenic.

So who and why

1. Wishful thinkers. The shut down is painful. It would be nice for it not to be necessary, so some people decide it is not necessary.

2. One of them is named Trump: I don’t pretend to understand him, but I think this is mostly infantile wishful thinking. He wishes there were no lockdown and no epidemic, so he believes it is possible. I am fairly sure this is also true of a majority of the small minority who thinks gatherings of 10 or more will be safe soon or in another 40 days.

3. Trump followers. I am sure that there would be even fewer advocates of reopening soon and no or very few demonstrations if Trump were’t against lockdowns. There are clearly many Americans who believe what he says and follow him blindly. I count the Fox News editorial staff among them. Fox follows Trump as he zigs and zags, and tens of millions of Americans follow Fox.

I am sure this is most of it, but I would like to go on.

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What has Science Established ?

I want to try to punch above my weight (and be a troll) and contest this

Dr. Kathryn Hibbert, director of the medical intensive care unit at Massachusetts General Hospital … said it will take weeks or months to get results and doctors and patients will need to wait for the results of the clinical trials before knowing which Covid-19 patients — if any — should be getting remdesivir.

“I think we should be extremely cautious about responding too enthusiastically to early data that has not been thoroughly vetted,” Hibbert said. “In the scientific community, over decades, we’ve established that critical review of clinical trials is the best way to determine if the data is strong enough to inform clinical decisions.”

I think the verb “establishd” is doing a lot of work here. Scientists have established two sorts of things.

One is the set of empirical results, styized facts and well supported theories. It is reasonable to accept that science has established that information can not be transmitted faster than the speed of light and that DNA (and topically for some viruses RNA are genentic materials.

The other is that scientists have established rules for what can be published peer reviewed journals (and rules for peer review) and Congress has established a Pure Food and Drug Act which authorizes the FDA to establish rules for which pharmaceuticals can be sold. There is a difference between natural laws and, you know, ordinary laws. Both are binding and both have been established, but one set is discovered and the other set is made.

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Two Cheers for the FDA

Only two because the FDA did play an important role in the US Covid 19 testing fiasco.

the first cheer is for extreme speed in approving phase 1 trials of candidate vaccines (vaccine in a person within 2 months of publication of the Sars Cov2 sequence) and phase III trials of Remdesivir (results leaking already) and hydroxychloroquine.

The second and even louder cheer is for the expanded access to Remdesivir policy. I actually predicted that this wouldn’t happen. I was wrong. I guessed there would be consideration of compassionate use in individual cases. I think the reason there is a systematic program is that the FDA and Gilead (the manufacturer) were overwhelmed with requests.

In particular, I note that one onlusion criterion is eligibility for a clinical trial. If one is eligible then one must risk getting the placebo. The logic is that people have the right to standard of care but do not have the right to an experimental drug which is more likely to help than to harm them. I argue for this logic here.

On the other hand, an exclusion criterion is “Requiring invasive mechanical ventilation (e.g., via endotracheal intubation or tracheostomy)”. This doesn’t make much sense. There is good reason to think that antivirals are useful especially if given early before the cytokine storm breaks. I think part of the logic here is first do no harm so an experimental drug can be used only on people who have very poor chances without it (the death rate of the intubated is roughly 66%). Also I guess Remdesivir will soon be in short supply (I think they have enough for 140,000 patients now and basically everyone in the world will want some).

So the expanded access is radical, but I don’t think it is radical enough.

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Premature Hydroxychloroquine After Action Report

The action sure isn’t over. The armies are still on the field, but I fear the outcome is no longer in doubt and hydroxychloroquine will lose this battle. There are two good studies which show almost exactly no benefit of hydroxychloroquine. They are reveiewed here. Basically the only benefit detected is as a nonspecific anti-inflamatory. There is essentially no evidence that hydroxychloroquine blocks replication of Sars Cov2 in people as it does in vitro.

I was an enthusiast for hydroxychloroquine so I have a lot of explaining to do. I will do it after the jump.

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hydroxychloroquine and Remdesivir Update

I have repeatedly argued that, based on in vitro evidence, hydroxychloroquine should be prescribed while we wait for the results of clinical trials. Such results were just published. They are very disappointing.

The link is to an LA Times Article: latimes.com 2020-04-17 malaria-drugs-fails-to-help-coronavirus-patients-in-controlled-studies

On the other hand
Early peek at data on Gilead coronavirus drug suggests patients are responding to treatment

The University of Chicago Medicine recruited 125 people with Covid-19 into Gilead’s two Phase 3 clinical trials. Of those people, 113 had severe disease. All the patients have been treated with daily infusions of remdesivir.

“The best news is that most of our patients have already been discharged, which is great. We’ve only had two patients perish,” said Kathleen Mullane, the University of Chicago infectious disease specialist overseeing the remdesivir studies for the hospital.

[skip]

“It’s always hard,” she said, because the severe trial doesn’t include a placebo group for comparison. “But certainly when we start [the] drug, we see fever curves falling,” she said. “Fever is now not a requirement for people to go on trial, we do see when patients do come in with high fevers, they do [reduce] quite quickly. We have seen people come off ventilators a day after starting therapy. So, in that realm, overall our patients have done very well.”

She added: “Most of our patients are severe and most of them are leaving at six days, so that tells us duration of therapy doesn’t have to be 10 days. We have very few that went out to 10 days, maybe three,” she said.

back to hydroxychloroquine and the very disappointing results

Quick summary of Tang et al pdf warning “The overall 28-day negative conversion rate was not [statisically significantly argg] different between SOC plus HCQ and SOC group (Kaplan-Meier estimates 85.4% versus 81.3%, P=0.341). ”

Conclusions The administration of HCQ did not result in a higher negative conversion rate but more alleviation of clinical symptoms than SOC alone in patients hospitalized with COVID-19 without receiving antiviral treatment, possibly through anti-inflammatory effects. Adverse events were significantly increased in HCQ recipients but no apparently increase of serious adverse events.

Mahevas et al was not a randomized controlled trial as explained by the title “No evidence of clinical efficacy of hydroxychloroquine in patients hospitalised for COVID-19 infection and requiring oxygen: results of a study using routinely collected data to emulate a target trial”

Results
This study included 181 patients with SARS-CoV-2 pneumonia; 84 received HCQ within 48 hours of admission (HCQ group) and 97 did not (no-HCQ group). Initial severity was well balanced between the groups. In the weighted analysis, 20.2% patients in the HCQ group were transferred to the ICU or died within 7 days vs 22.1% in the no-HCQ group (16 vs 21) events, relative risk [RR] 0.91, 95% CI 0.47–1.80). In the HCQ group, 2.8% of the patients died within 7 days vs 4.6% in the no-HCQ group (3 vs 4 events, RR 0.61, 95% CI 0.13–2.89),and 27.4% and 24.1%, respectively, developed acute respiratory distress syndrome within 7 days (24 vs 23 events, RR 1.14, 95% CI 0.65–2.00). Eight patients receiving HCQ (9.5%) experienced electrocardiogram modifications requiring HCQ discontinuation.

The comparison doesn’t just fail to reject the null that hydroxychloroquine doesn’t help. the outcomes are very similar with and without. It sure suggests any possible benefits are very small (recall the warning that this wasn’t a randomized trial).

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Economic Policy for the Pandemic III What About Aggregate Demand ?

Unemployment has shot up in many countries especially including the USA. Is it time for aggregate demand stimulus ? One interesting thing (noted by Krugman in his newsletter which should still be a blog) is that Keynesians (including Krugman) are not treating everything as a nail, because all they have is a hammer. He (and others) haven’t just reflexively said stimulate until the unemployment rate is normal. This might be a bit of boasting about not making a stupid mistake, because the straw Keynesian demanding full employment now would be very dumb. Much (but not all) of the high unemployment is socially desirable. It is the result of the technology shock that, right now, the provision of services to customers carries the unusual cost of sharing Covid 19. So baristi and waiters should stop working. Their sitting at home is not a waste of productive capacity — it is an efficient response to the pandemic.

But note the parenthetical “(but not all)”. I will argue that it is also true that, in addition to the efficient unemployment caused to reduce contagion, there is also inefficient unemployment due to low aggregate demand. This means that stimulus makes sense. This includes cutting interest rates back to zero again and also broad fiscal stimulus including the $1200 which many of you may have received today. The reason is that the loss of income from currently socially undesirable work (tending bar and waiting tables and such) causes a larger decline in total production through the good old Keynesian multiplier. That additional decline is inefficient and can be prevented with monetary and fiscal aggregate demand stimulus.

This is so obvious that it is even obvious to Donald Trump. Or rather this is a point where Trump, Pelosi and Krugman agree so it must be obvious. I am going to play with some counter-intuition explaining how it can be non obvious to someone who knows a little general equilibrium theory but missed developments in the field since 1950 (I am thinking of fresh water macroeconomists who have been very quiet lately).

I realize that this post makes an obvious point in a boring technicl way so I put all the rest of it after the jump.

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Economic Policy for the Pandemic II

I am going to attempt a briefer clearer version of this post

I am interested in critiquing (and mostly praising) the CARES Act and discussing what still needs to be done. I think my points (if any) are that an extraordinary unforseen crisis simplifies some issues and relaxes some constraints. I will now go by topic

1. Aid to the unemployed. There are sudddenly many more people without market income. They need help. Here I applaud the decision to give the unemployed an extra $600 a week rather than increase the replacement ratio of unemployment insurance. This was done, because it is simple and it is possible to get the money to households quickly, but I also think it is better targetting.

Consider two workers with different salaries who suddenly lose their jobs. Is it better to give the worker who had a higher salary more when both are unemployed ? Just giving the same amount to all unemployed people implies a more equal distribution of income among the unemployed which implies higher average utility. Normally, this isn’t the only consideration, because an excessively high replacement ratio distorts incentives. In particular 4 Republican Senators were convinced that the CARES act contained a drafting error as it implied some people would have higher income when unemployed than when employed. Normally this is a problem (even though workers who quit don’t get unemployment insurance) because such generous benefits discourage job search and cause workers to turn down job offers. This is not currently a problem. First job search is a possible cause of contagion. Incentives to just sit at home are often optimal right now. Second, there isn’t a long term reallocation of labor problem. Many unemployed workers can and should return to their old jobs when the pandemic ends. This very much simplifies their problem and implies that they don’t need to be given incentives to find entirely new jobs.

This also means that I think the benefit should go to households where no one was employed in 2019. Here again incentive problems are minor. They too should be sitting at home now. They too will not make plans for the future expecting all this to be repeated. This means I am advocating reversing the 1996 Welfare reform (as I always do).

I think in this case the crudest utilitarian calculus is best — to each as he has need — not to each such as he has need and is incentive compatible.

Another issue is whether to bail out firms and, if so, whether to loan at a penalty rate, at a normal rate, or just give them cash. Here the point is that firms face bankruptcy even if they are viable in normal times and therefore solvent and even if their managers didn’t make mistakes. There is no need to punish people for a disaster which no one foresaw. My point (if any) is that there is no need to reward them either.

Normally, I would like to take from wealthy proprietors of small firms. Again this is pure vulgar utilitarian egalitarianism. Normally, this is a bad idea, because one can’t credibly promise to do it just this once. Once off redistribution from rich entrepreneurs can add to utility, but the threat of future redistribution discourages business enterprise. Again, this is not a problem right now. There isn’t a legal or constitutional restriction on imposing tough conditions on a bailout — participation is voluntary. There is a low incentive cost of not rewarding effort and risk taking when there is an unforseen disaster. (the word unforseen is doing all the work there).

So again, I think this is time for simple vulgar egalitarianism. I would take from shareholders, because they are rich. I would take from individual proprietors because they are rich. So I would make the terms of the bailout harsh, because such policy is taking from those who have a lot.

In particular, I think the Treasury should get an equity stake and so a share of the upside risk. I support this here and now, because I support this everywhere and always. The only unusual thing is that, because firms need cash, I now propose buying newly issued shares not buying shares on the market. But here too the right price to pay is the market price, not the market price plus a gift to the rich. That means a low price if a firm desperately needs liquidity now.

So new shares sold at firesale prices. The reasons for the low price, that is harsh bargain, are the usual reasons — paying more than one has to pay distorts incentives, and giving to the rich is inefficient. The first consideration is relatively minor if the policy is a response to a genuine unexpected exogenous event, but it doesn’t switch sign.

So I say it’s time to drive a tough bargain, time to lend freely at a penalty rate or, even better, time for the state to demand an equity stake in firms (and ban share buybacks and limit managment compensation). I think this becase I think it is always time for the state to demand an equity stake in all firms, ban buybacks and limit compensation. But I can also argue that if these provisions are conditions on a voluntary bailout transaction that the usual case against them is very much weaker than usual.

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Remdesivir V

This is interesting. In addition to the two huge multi center phase III trials of Remdesivir for Covid 19 with estimated completion some time in May 2020, there is a smaller but very large trial in Beijing with estimated completion May 1 2020. The East is Remd ! May Day May Day May Day
“Estimated Study Completion Date : May 1, 2020”

Finally there is a very large trial in Hubei province with estimation completion date April 27 2020
“Estimated Study Completion Date : April 27, 2020”

Also there is expanded access already. This is instead of individual requests or compassionate use. Note that one exclusion criterion is eligibility for a controlled trial — people will have to risk getting placebo, because they are eligible for a trial.

I think this is ethical. You read it here.

On the other hand, they only have enough Remdesivir for 30,000 patients

we have proactively and rapidly scaled our supply chain. As of late March, using the active ingredient we already had in our inventory, we have increased our supply to more than 30,000 patient courses of remdesivir on hand, assuming a 10-day course of treatment for patients.

The synthesis takes time and requires reagents which are in short supply, so they can’t scale up immediately

Our goal is to produce a total of:

More than 140,000 treatment courses by the end of May 2020
More than 500,000 treatment courses by October 2020
More than 1 million treatment courses by December 2020
Several million treatment courses in 2021, if required

Capacity Expansion through External Manufacturing

We have supplemented our internal manufacturing with significant additional capacity from multiple manufacturing partners in North America, Europe and Asia. Through these efforts, we believe we have created a manufacturing network capable of producing large volumes of remdesivir at the fastest pace feasible.

I think this is a case for some Defence Production Act_ion.

Update: it seems the 1.5 million doses for over 140,000 patients are available already. Gilead seems to have under promised and over delivered. https://www.statnews.com/pharmalot/2020/04/05/gilead-covid19-coronavirus-remdesivir/

Update2: more evidence that Remdesivir works . This is a leak of preliminary data from one of the phase III trials.

“Remdesivir was a miracle” — Slawomir Michalak Covid 19 Survivor

I told you “possibly so”. Actually checking I see that I did not predict teh expanded access program. I guessed individual requests for compassionate use. So I was wrong about what would be done. I should applaud the FDA for being more flexible than I guessed they would be

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