And From the Boffins

In a Wall Street Journal op-ed Scott Gottlieb reports on prospective treatments for COVID-19:

Even if new cases start to stall in the summer heat, the virus will return in the fall, and so will fresh risk of large outbreaks and even a new epidemic. People will still be reluctant to crowd into stores, restaurants or arenas. Schools may remain closed. The public’s fears won’t relent simply because there are fewer new cases. We’ll be running an 80% economy.

The only way out is with technology. Aggressive surveillance and screening can help warn of new infection clusters that could turn into outbreaks, but that won’t be enough. A vaccine could beat the virus, but there won’t be one this year. The best near-term hope: an effective therapeutic drug. That would be transformative, and it’s plausible as soon as this summer. But the process will have to move faster.

Americans would have the confidence to return to work, even if the virus is still circulating in the fall, if they knew that a robust screening system is in place to identify and arrest new outbreaks and medication can significantly reduce the chance of becoming severely ill. Kevin Warsh, a former Federal Reserve governor, estimates that such a drug could restore at least $1 trillion in economic activity.

Given the enormous public-health and economic stakes, it is worth doing whatever it takes to move such a drug to market. There are two promising approaches, and both could be available soon if government and private industry do things right. It’s time to place some firm bets and put resources behind these experimental treatments.

One approach involves antiviral drugs that target the virus and block its replication. Think of medicines for treating influenza, HIV or cold sores. The drugs work by blocking the mechanisms that viruses use to replicate. Dozens of promising antiviral drugs are in various stages of development and could be advanced quickly. The one furthest along is remdesivir, from Gilead Sciences. There’s evidence from clinical experience with Covid-19 patients that it could be effective.

The other approach involves antibody drugs, which mimic the function of immune cells. Antibody drugs can be used to fight an infection and to reduce the risk of contracting Covid-19. These medicines may be the best chance for a meaningful near-term success.

Antibody drugs are based on the same scientific principles that make “convalescent plasma” one interim tactic for treating the sickest Covid-19 patients. Doctors are taking blood plasma from patients who have recovered from Covid-19 and infusing it into those who are critically ill. The plasma is laden with antibodies, and the approach shows some promise. The constraint: There isn’t enough plasma from recovered patients to go around.

Antibody drugs are engineered to do the same thing as convalescent plasma, but because they’re synthesized, they don’t depend on a supply of antibodies from healed patients. Biotech companies would manufacture them in large quantities using recombinant technology, the same approach behind highly effective drugs that target and prevent Ebola, respiratory syncytial virus and other infections. The antibodies can also be a prophylaxis given to those exposed to Covid-19, or to prevent infection in vulnerable patients, such as those on chemotherapy. These drugs could protect the public until a vaccine is available.

The biotech company Regeneron successfully developed an antibody drug to treat Ebola as well as one against MERS, a deadly coronavirus similar to Covid-19. Regeneron has an antibody drug that should enter human trials in June. Vir Biotechnology is also developing an antibody treatment for Covid-19 and says it could be ready for human trials this summer. Amgen recently started its own program with Adaptive Biotech and Eli Lilly has one as well. If these approaches work, the drugs can advance quickly, because much of the science and the safety is already well understood.

The greatest emphasis is likely to be on things that are patented or can be patented. If there is any prospect that something that isn’t patented or patentable has any applicability we should jump all over it. My point is not to boost one therapy over another, only that we shouldn’t sneer at inexpensive treatments.

Let many flowers bloom. A treatment effective in a minority of cases that can be approved and manufactured in quantity quickly is better than one that can’t be approved or manufactured on a timely basis, however effective it might be. You deploy the one until the other comes along.


Wear Masks!

It’s a science experiment!


COVID-19 Action Plan With Chinese Characteristics

In an op-ed in the New York Times Hong Kong epidemiologist provides a frank assessment of the status of our global efforts against COVID-19:

A formal framework is needed, with an explicit rationale grounded in science, for determining when and how and based on what factors to relax restrictions — and how to reapply some or all of them should another epidemic wave hit again.

Containment has failed everywhere. In some places — Wuhan in February; northern Italy in March — the epidemic spread so quickly that the relevant authorities had to focus mainly on mitigating its effects, on damage control. In other places, suppression has worked so far: Hong Kong, Singapore and Taiwan have not experienced sustained local epidemics. Not yet, at least.

and here’s his plan of action:

Here is a formal framework for how governments could monitor the state of this pandemic much more accurately than many seem to be doing now, and how then, acting on the evidence, they could tune their interventions quickly enough to stay ahead of the outbreak trajectory.

For starters, one needs robust data. Policy must not be determined based on the daily count of reported cases ­— the tallies you read about constantly in the news — because those are unreliable. What’s needed instead is the coronavirus’s real-time, effective reproduction number, or its actual ability to spread at a particular time. And one needs to understand that number properly, in context.

The rate at which a virus is transmitted — known as the R-naught (R0), or basic reproductive number — refers to the average number of people to whom an infected person passes on the virus in a population with no pre-existing immunity. The R0 can vary from place to place because of the population’s age structure and how frequently people come into contact with each other.

The “effective” version of that number, the Rt — or the reproductive number at time “t” — is the virus’s actual transmission rate at a given moment. It varies according to the measures to control the epidemic — quarantine and isolation protocols, travel restrictions, school closures, physical distancing, the use of face masks — that have been put in place.

Daily reported cases do not convey the true state of the virus’s spread. For one thing, there is so much heterogeneity in the per capita testing capacity of countries around the world that it would be foolhardy to try to draw any broad conclusion about the virus’s transmissibility from all that disparate data. For another, the figures for reported cases lag actual infections by at least 10 to 14 days.

That’s because the incubation period for Covid-19 is about six days. And because — partly given shortages of test kits in many countries — some people don’t ever get tested, and those who do probably don’t until they have displayed symptoms for a few days.

However, it is possible to bring the daily count of reported cases closer to the real-time Rt thanks to both statistical adjustments and digital analytics.

The School of Public Health at the University of Hong Kong has been estimating, and publishing, the real-time Rt for Hong Kong since early February. The chart is based on the epidemic curve corrected by established statistical methods to reduce the time lag between the onset of infection symptoms and the official reporting of new cases. (The result is called “nowcasting.”) We hope to soon be able to further enhance these estimates by incorporating location-based data from the Octopus card that many Hong Kongers use to pay for public transport or to shop.

In China, the location-based functions of the online payment platforms of Alibaba, Baidu and Tencent could be used to track people’s activity. In the West, data feeds from Facebook and Google could geo-code online searches and payments. Citymapper, a mapping and public transit app, follows people’s movements in major cities in real time.

Activity data mined from all these apps and platforms, as well as records from payment cards, could be used to determine how people mix — which in turn could be used to infer the likelihood of their passing the virus around. In a recent contribution to the journal Science, Caroline Buckee described how all this data could be marshaled to chart a real-time map analyzing how physical distancing policies are affecting people’s movements.

With a bit of ingenuity, existing digital tools can quickly be turned into epidemic-monitoring instruments — and without intruding into people’s lives. Those who, as a general matter, worry about invasions of privacy (and rightly so) need not in this case: The idea is to only study aggregate, and therefore anonymous, numbers — to look at big data, not at personal information or anyone’s identity.

Then, having determined what the Rt actually is, decision makers could more precisely adjust their interventions to keep that number at what is, for them and their constituencies, an acceptable level.

An Rt of 1 means that the epidemic is holding steady: For every person who is infected, another one becomes infected, and as the first one either recovers or dies, the second one replaces it; the size of the total pool of infected people remains the same. At a rate below 1, the epidemic will fade out. Above 1, it will grow, perhaps exponentially.

That said, an Rt of 1 or below will not do in all circumstances. Context matters, too.

An Rt of 1 might be acceptable in a place with 10 million people if, say, no more than a couple of dozen new infections are confirmed every day. But it wouldn’t be if an epidemic were raging there and several hundred or thousands of new cases occurred daily. In the face of an explosive outbreak, the authorities would first need to take a sledgehammer to the Rt to knock it down to a very low level — 0.1 or 0.2 — and maintain it there for as long as it took to bring the daily case count down to a manageable figure.

In other words: Each community must determine the real-time effective reproductive number it can accept given its own circumstances, in particular the stage of the epidemic it is at.

Still, for all communities that determination essentially requires doing the same thing: Figuring out the number of new daily infections that their health system can handle without imploding.

Imagine a city that has 1,000 beds in intensive care units. It cannot have more than 1,000 people on a respirator at any given time. If the average length of a patient’s stay in the I.C.U. is 14 days, this city cannot provide intensive care for more than about 71 new patients a day (1,000 / 14 = 71.42). Assuming that about 5 percent of all newly infected cases are so severe as to require intensive care, then the city cannot afford to have more than a total of about 1,420 new infections a day (71 x 20 = 1,420). This is the true number of infections, only a fraction of which are reflected in the officially reported count.

The authorities, having established the number of new infections the city’s emergency health facilities can support, can then determine what Rt they should aim for and tune their interventions to reach it.

Next, once it is clear what the health care system can bear, one must ask what the economy and, separately, what the people, can accept.

Even if the health care system can just about tolerate 1,420 new infections a day, would Wall Street? Would the financial markets — and, more important, the real economy — be spooked? Or react as they do during a bad flu season?

And how long can the population accept the restrictions required to maintain that level of infections? Will people stop complying? Are their mental and emotional well-being being jeopardized?

My first observation about that is that I think he’s whistling in the dark. At the present low volume of recoveries, no action to reduce spread will prevent the health care system from being overloaded. The best that can be expected is to delay that point long enough to expand the available resource and a lot of the barriers preventing that now are regulatory.

My second observation is that in the United States at least we reached the end of the line on his plan

And how long can the population accept the restrictions required to maintain that level of infections? Will people stop complying? Are their mental and emotional well-being being jeopardized?

before it even began. Compliance has never been and will never be good enough for any suppression strategy to work, at least not until the recovery time can be shortened substantially.

Now let me air a peeve. The present method being used to treat COVID-19 patients is not scientific. It’s based on commonsense and the standard of care. Does it work in the majority of cases? Nobody really knows. It certainly hasn’t been subjected to the kind of scrutiny that the medical Powers-That-Be are demanding of other alternative treatment. For one thing it would be unethical to do so.

What should we do? I have no idea but I can make some suggestions. First, enlist the American people in what they should do rather than relying on limiting what they are allowed to do. Get volunteers making masks in the tens or hundreds of millions. There are a half million 3D printers in the U. S. alone capable of making N95 masks. The limitation there will be materials. Use the Defense Production Act more aggressively to get companies producing the necessary materials, not just for masks and respirators but for all of the things that will be necessary to treat COVID-19. We don’t produce enough of those things domestically and we can’t rely on other countries for them. They all have problems of their own. Waive requirements including environmental requirements. Get all of the many levels of government pulling in the same direction. There’s a role for the federal government in that but if we depend on the federal government for it, it’s a cop out. We’ll fail.

Get the companies whose business model consists of gathering information to do what they do best—gather information. Dragoon them into it, if necessary.

We need to respond to COVID-19 in the American way which is not to endure the hardships it imposes but to refuse to endure the hardships it imposes and do something about them. Rely on passive compliance in places where that will work.


Dispatches from the Front

I don’t have much to say about it but there’s an op-ed well worth reading at the Washington Post, written by a physician whose job it is to clear the ventilators of COVID-19 patients in hospital:

It’s a powerless feeling, watching someone die. The oxygen level drops, the heart rate drops, the blood pressure drops. These patients are dying on the ventilator, and sometimes when they take away the body, the tube is still in the airway.

It isn’t that often that you read something approximating despair but this comes too close for comfort.


Longer Than They Think

This prediction at STAT sounds about right to me:

Public health experts are increasingly worried that Americans are underestimating how long the coronavirus pandemic will disrupt everyday life in the country, warning that the Trump administration’s timelines are offering many a false sense of comfort.

It would be interesting to know the operative definition of “everyday life” or “returning to normal”. I think that at a first approximation we will never return to normal or, perhaps more precisely, what is perceived as normal has changed.

I found this grimly amusing:

Experts say even a return to normal could come with asterisks. Mina noted, for instance, that restaurants may need to put more space between tables. Others have suggested people in high-risk groups — those over 65 or 70 and people with chronic conditions — may need to practice physical distancing even after restrictions have loosened for others, at least until vaccine is ready.

Ignoring the legal problems in the last sentence, the “experts” appear to be unaware that restaurants (the ones that actually have tables) gauge their prospective revenue based on the number of people they seat and how many times per day that can be turned over.

Restaurants tend to operate on very tight margins at the best of times and reducing the prospective revenue by 10% is likely to mean the difference between a money-losing hobby and something from which one can make a living. My offhand guess is that sit-down restaurants may become a thing of the past, particularly in places with very high real estate costs per square foot, like New York or San Francisco. The hospitality sector in general could be, if not doomed, a shadow of its former self.

When you recognize how many of the “working poor” work in just those sectors, it really makes you wonder what “normal” will look like.

And this sounds like a free flight of fantasy to me:

“We need an army of contact tracers in every community in the U.S. to be ready to find every contact and warn them to care for themselves and stop spreading it to others,” he said.

We are not China. Regardless of the risks we will not have paid informers in every block tracking people. Who would pay for such a thing? It would necessarily be financed locally. Why should the residents of Marfa, Texas pay for contact tracing in New York City? Nine of the ten most densely-populated towns in the country are in the New York metro area (the other is in LA).

Last observations:

  • I’d have a lot more confidence in that 18 month estimate for a vaccine if a vaccine for any coronavirus had ever been produced. What if a vaccine is never produced?
  • The cost of contact-tracing increases exponentially with the population density.
  • Just because you’re an expert in something does not mean you’re an expert in everything.
  • We really need to start talking about risk tolerance. Different people have difference levels of tolerance for or ability to accept risk. In general the poorest have the least ability accept increased risk. Let’s not lose track of that in a panic-stricken rush towards a risk-free world.

Testing a Random Sample

Finally. Somebody stating what is obvious to me. From The Hill:

John Ioannidis, a Stanford epidemiologist who is famous for debunking bad research, has been pushing for it. He told me that random sampling is needed and could be done with a couple of thousand tests. When I told him that I previously worked in the polling industry, he put it in terms that resonated with me. He said, “Random representative testing is like polling. We run thousands of opinion polls in this country. We should similarly get a representative sample of the population and get them tested. It is just so easy.”

A recent television interview with Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases and member of the White House Coronavirus Task Force, underscores the need. After estimating that 100,000 to 200,000 Americans could die of the coronavirus, he said that projections are a “moving target” and that models are “only as good and as accurate as your assumptions.” But how good are models if the data is insufficient?

Ioannidis warned of a potential evidence fiasco in a recent op-ed for Stat. He wrote, “The data collected so far on how many people are infected and how the epidemic is evolving are utterly unreliable. Given the limited testing to date, some deaths and probably the vast majority of infections due to SARS-CoV-2 are being missed.”

Eran Bendavid and Jay Bhattacharya, also professors at Stanford, echoed that concern in The Wall Street Journal, writing, “The true fatality rate is the portion of those infected who die, not the deaths from identified positive cases.” They speculate that due to how infectious the coronavirus appears to be, and because tens of thousands of people traveled from Wuhan to America in December, millions of Americans could have been infected.

Random sampling will tell us what percentage of the population has the coronavirus and its lethality. Only testing the very sick skews mortality rates and leaves us in the dark about how many Americans are unknowingly walking around asymptomatic or with mild symptoms. Looking at other countries’ data also has its challenges; age structures, climate differences, quality of health care systems and testing all vary.

New York State has administered nearly a quarter million COVID-19 tests, by far the largest number per 1M population of any state. Nearly two-thirds of its cases are in the counties surrounding New York City. Administering just a few thousand of those tests to a random sample of people in the Bronx, Queens, Manhattan, Kings County, etc. would have probably been more productive than the vast majority of those tests. Epidemiological testing is long overdue.

I have a question for physicians. In the absence of a treatment for COVID-19, how does testing a patient with the symptoms of COVID-19, change how you treat that patient? I doubt that it actually does. I think the same supportive care would be provided, as available, whether the test was positive or negative.



What conclusions should we draw from this account of the story of testing for COVID-19 in the United States, published in the Houston Chronicole? I think it’s summed up pretty well in one quote, from an exasperated researcher:

“The most pernicious effect of the current regulatory environment is that it kneecaps our ability for preparedness should a true emergency emerge,” Greninger wrote to colleagues on Feb. 14.

or maybe the conclusion of the article:

On March 12, Fauci, who runs the National Institute of Allergy and Infectious Diseases, told lawmakers the problem was not simply the failure of the CDC test. The coronavirus testing debacle had exposed deep structural problems in the nation’s public health system, he said.

“Yeah, it is a failure, let’s admit it,” he said. “The idea of anybody getting it easily the way people in other countries are doing it, we’re not set up for that. Do I think we should be? Yes, but we’re not.”

Bureaucracts and political appointees may have succeeded in killing thousands of Americans.


Test Sewage

I found this article in Scientific American fascinating:

More than a dozen research groups worldwide have started analysing wastewater for the new coronavirus as a way to estimate the total number of infections in a community, given that most people will not be tested. The method could also be used to detect the coronavirus if it returns to communities, say scientists. So far, researchers have found traces of the virus in the Netherlands, the United States and Sweden.

Analysing wastewater—used water that goes through the drainage system to a treatment facility—is one way that researchers can track infectious diseases that are excreted in urine or faeces, such as SARS-CoV-2.

One treatment plant can capture wastewater from more than one million people, says Gertjan Medema, a microbiologist at KWR Water Research Institute in Nieuwegein, the Netherlands. Monitoring effluent at this scale could provide better estimates for how widespread the coronavirus is than testing, because wastewater surveillance can account for those who have not been tested and have only mild or no symptoms, says Medema, who has detected SARS-CoV-2 genetic material—viral RNA—in several treatment plants in the Netherlands. “Health authorities are only seeing the tip of the iceberg.”

The TL;DR version of the article is that maybe we should put less emphasis on testing individuals for COVID-19 and more on testing their sewage. Something to think about.


After COVID-19

Henry Kissinger weighs in on the COVID-19 outbreak in an op-ed in the Wall Street Journal:

The coronavirus has struck with unprecedented scale and ferocity. Its spread is exponential: U.S. cases are doubling every fifth day. At this writing, there is no cure. Medical supplies are insufficient to cope with the widening waves of cases. Intensive-care units are on the verge, and beyond, of being overwhelmed. Testing is inadequate to the task of identifying the extent of infection, much less reversing its spread. A successful vaccine could be 12 to 18 months away.

The U.S. administration has done a solid job in avoiding immediate catastrophe. The ultimate test will be whether the virus’s spread can be arrested and then reversed in a manner and at a scale that maintains public confidence in Americans’ ability to govern themselves. The crisis effort, however vast and necessary, must not crowd out the urgent task of launching a parallel enterprise for the transition to the post-coronavirus order.

Ever the consummate courtier. Much of the op-ed focuses on what should happen after the crisis is over:

Drawing lessons from the development of the Marshall Plan and the Manhattan Project, the U.S. is obliged to undertake a major effort in three domains. First, shore up global resilience to infectious disease. Triumphs of medical science like the polio vaccine and the eradication of smallpox, or the emerging statistical-technical marvel of medical diagnosis through artificial intelligence, have lulled us into a dangerous complacency. We need to develop new techniques and technologies for infection control and commensurate vaccines across large populations. Cities, states and regions must consistently prepare to protect their people from pandemics through stockpiling, cooperative planning and exploration at the frontiers of science.

Second, strive to heal the wounds to the world economy. Global leaders have learned important lessons from the 2008 financial crisis. The current economic crisis is more complex: The contraction unleashed by the coronavirus is, in its speed and global scale, unlike anything ever known in history. And necessary public-health measures such as social distancing and closing schools and businesses are contributing to the economic pain. Programs should also seek to ameliorate the effects of impending chaos on the world’s most vulnerable populations.

Third, safeguard the principles of the liberal world order. The founding legend of modern government is a walled city protected by powerful rulers, sometimes despotic, other times benevolent, yet always strong enough to protect the people from an external enemy. Enlightenment thinkers reframed this concept, arguing that the purpose of the legitimate state is to provide for the fundamental needs of the people: security, order, economic well-being, and justice. Individuals cannot secure these things on their own. The pandemic has prompted an anachronism, a revival of the walled city in an age when prosperity depends on global trade and movement of people.

Sadly, I think it’s superficial. Is is possible that people have little confidence in our institutions because of their repeated failures? And that failure along a single plane—the benefit of those in charge. What I think we have witnessed is a panic among political leaders and what we should have learned is that we cannot afford to allow supply chains for vital goods to run through large, powerful authoritarian countries. It isn’t even that difficult. All that would be required in the case of health care, for example, is for the only goods eligible for compensation through Medicare or Medicaid would need to be made in the United States from components with completely American supply chains. Strict liability for fraudulent claims. Yes, it would increase costs and probably cut margins. You’d probably be surprised at how quickly production can be repatriated.

Enlightenment values do not require us to sacrifice our populations and our security on the altar of globalism.


Test Or Bust

In op-ed at the Wall Street Journal Paul Romer and Rajiv Shah highlight the importance of testing:

For now, social distancing is the best America can do to contain the Covid-19 pandemic. But if the U.S. truly mobilizes, it can soon deploy better weapons—advanced tests—that will allow the country to shift gradually to a protocol less disruptive and more effective than a lockdown.

Instead of ricocheting between an unsustainable shutdown and a dangerous, uncertain return to normalcy, the U.S. could mount a sustainable strategy with better tests and maintain a stable course for as long as it takes to develop a vaccine or cure. The country will once more be able to plan for the future, get back to work safely and avoid an economic depression. This will require massive investment to ramp up production and coordinate the construction of test centers. But the alternatives are even more costly.

Two types of testing will be essential. The first test, which relies on a technology known as the polymerase chain reaction, or PCR, can detect the virus even before a person has symptoms. It is the best way to identify who is infected. The second test looks not for the virus but for the antibodies that the immune system produces to fight it. This test isn’t so effective during the early stages of an infection, but since antibodies remain even after the virus is gone, it reveals who has been infected in the past.

Together, these two tests will give policy makers the data to make smarter decisions about who needs to be isolated and where resources need to be deployed. Instead of firing blindly, this data will let the country target its efforts.

We’ve got to do more, faster. Local, state, and federal governments need to clear the path and use the powers at their disposal to accomplish more testing. The first priority will necessarily be health care workers. Then onwards to the whole population.

Waiting six months to mobilize such an effort is far too long. We’ve got days or, at the most, weeks, not months and years.