In Case of Fire, Break Glass

We are now more or less into our sixth month of the SARS-CoV-2 epidemic (the novel coronavirus that is at the heart of COVID-19). As of today, the estimated number of infected Americans is just over six million, and between 175,000 (official state departments of health) and 185,000 (Johns Hopkins University) have lost their lives.

Unfortunately, this outbreak early on itself became infected with politics, and sides quickly were chosen and battle lines drawn.

It's an election year, so some of this is to be expected.

Fights about shelter in place orders, mask wearing, possible therapies, vaccine developments, how to measure the impact economically and medically, and myriad other battles were launched.

Recently a thread has appeared, quietly at first, but over the past few days, it has gathered momentum.

According to a weekly report issued by the US Centers for Disease Control and Prevention (CDC), somewhere on the order of 94 per cent of people who died with COVID-19 had one or more underlying conditions.

Many seized on this to claim that the epidemic is grossly overblown, and that "only" six per cent of those who died with confirmed SARS-CoV-2 infection died "from COVID-19." Something of a semantic debate has been going on for months about the differences between dying from COVID-19 (i.e., that the virus itself caused death) and dying with COVID-19 (you died from something else, and COVID-19 was just on board). The recent publication has caused the debate to reignite, and with more heat.

I am not a virologist or infectious disease doctor. I don't see or treat patients. I'm not a coroner or a medical examiner. It's not my job to assign cause of death.

I'm also not a politician who is looking at a tough re-election, or a challenger looking to parlay the pandemic into a means of election. Nor am I a political operative or pundit who gets paid to sway public opinion one way or the other.

I am an epidemiologist.

It's (part) of my job to look at health data from a public or population health perspective. Moreover, I spent several years working on research in both hepatitis-C (Hep-C) and HIV disease. I've seen and participated in all sorts of analyses - disease transmission models, outcomes research, interventional impact analyses. 

Mortality modelling.

No-one knows for certain how many people at this point have actually been exposed, how many have been infected, or how many have actually died. With or due to COVID. We have estimates, and we have models on top of data. 

I do know this, however.

Whether the 94% statistic is accurate, and whether people with comorbidity (what in my world is the term used to describe "underlying conditions"), you need to take the estimates of death seriously. You need to look at claims that, because "only six per cent of people who died had no underlying conditions" the problem is being made larger than it is, or that you can ignore the threat.

The truth is that a huge number of Americans over the age of 18 has underlying conditions. It is possible - even likely if you are over 40 - that you have at least one. 

I know that I do.

Here is a paper published last month from the CDC on the prevalence of various chronic conditions in the US (https://www.cdc.gov/mmwr/volumes/69/wr/mm6929a1.htm#contribAff). The authors looked at a selected set of conditions believed to be associated with COVID mortality, including diabetes, obesity, heart disease, kidney disease, and chronic obstructive pulmonary disease (COPD). Data in various states, in cities and rural areas, were examined for people over the age of 18.

The research indicated that forty percent of the adult population had one or more of these conditions.

Two out of four.

The numbers turned out to be higher - close to 50% - in rural counties than in large, urban centres (39%).

Worse, prevalence rises with age. Far fewer people in their 20s had comorbidity than those over 50.

The arguments you are hearing that COVID-19 is not a serious problem because it, alone, has killed only six per cent of the 175-185,000 people are at best mistaken and at worst deliberately dishonest.

Please take the threat of COVID-19 seriously. Because the threat is serious. It is real.

Luckily, you are not helpless. As I said months ago at the outset, we are not helpless victims of fate. The final trajectory of SARS-CoV-2, its impact on you and people you care about is something you can affect. Your choices still matter. You can still have an impact.

Be smart.

Stay home unless you have to go out.

If you're going to be out, distance from other people if you can.

And if you can't, wear a mask.

A Simple Plan

I've (intentionally) kept quiet about the unfolding story that has been able to move COVID-19 off the front pages. Off the back page, and all the pages in the middle, to be honest.

On it's face, it's a really simple story. An old one.

About a week ago, the police in Minneapolis, Minnesota were called in to deal with what has been alleged as an incident where a middle-aged man - one not far away from my own age in fact - tried to buy some cigarettes with a counterfeit $20 bill. What happened in the time between the call and the terrible outcome is at this point, lost. But we all know how the encounter ended.

The video of Minneapolis police officer Derek Chauvin sitting with his knee on the back of a prone George Floyd in the last minutes are difficult to watch. Floyd can be heard gasping and begging for his life, at one point calling out to his mother. The officer's expressionless face stares ahead. His eyes - dead eyes - glare at the camera.

Officer Chauvin killed George Floyd with what can, at best, be described as a casual indifference.

Over the past week, protests have erupted across the country, many of them violent. Stores have been destroyed. People hurt - some killed - in spasms of violence.

I haven't had too much to say because, quite frankly, what is there to say?

The bottom line is that Chauvin killed Floyd. Floyd did not lose his life; it was taken from him.

I *really* have zero interest in debating the propriety of the destruction, and less interest in arguing about the looting. Whether it is local people, or left-wing "antifascist" (sic) actvitsts or "white nationalists," it's all the same to me.

I do not condone violence and crime. I live in central San Francisco, which has seen significant violence over the past couple of days. Helicopters buzzed overhead last night, and businesses on my street were boarded up. So I really am in absolutely no mood to be lectured by people living in suburban sinecures about "understanding" crime. I am just interested that my home and family remain safe. I do not have the luxury of social media preening the way many do.

With respect to politics, I will make a simple plea - I think politicians want to try to smear their political opponents rather than own up to their own guilt. That's what they do. Sorry. So I'm not here to argue whether the president is a fascist or the governor of Minnesota is weak. Pretty much everyone is going to retreat to their own priors on this one, as they always do.

What I want to say is this very simple thing.

I don't like a lot of rules; I never had. As a kid, I got into a lot of trouble because it was not in my nature to do something because "I told you so." I spent a fair amount of time in the principal's office because of it.

But I have most of my life been a supporter of law and order. The laws should be few; they should be clear. And they should be enforced fairly.

This goes especially for the police, and what happened in Minnesota was not just. It was not fair. And the cops who participated need to be held to account.

I think that there is simply no way one can watch what happened and not come away with the conclusion that the killing of George Floyd by four police officers (and they are all guilty in my book) was a crime. And our law officers if nothing else must uphold the law. There are just no two ways about it.

I've heard more than one argument about how many white men are killed by police, how many black men are killed by other black men. I am a mathematician; I know what an odds ratio is. It's beside the point. I have very, very little doubt that in this case, if George Floyd were white, he would likely be alive. This needs to be acknowledged. Our police are just not doing a good job enforcing the laws fairly. I know it. You know it. Yes, you do.

Let me tell you a little story. Many, many years ago, I got caught by the CHP speeding on the 280 freeway (a highway that runs south from San Francisco to San Jose, California). I was at the time living in Cupertino, so I must have been 25 or 26 years old at the time. I was late coming home to meet a friend for dinner, so my eye was not really on the speedometer so much as it was on the clock. A motorcycle cop hiding under the CA-87 flyover appeared and pulled me over. In those days, the speed limit in California was still 55, and I was easily going about 80. He wrote me the ticket, and I had a date with the dreaded "traffic offender school." Yes; it's a real thing in California.

So I got up at 6.30 in the morning one Saturday and headed off to 8 hours at Mission College in Santa Clara to make amends. One of the things we all were forced to do at the outset was stand and confess our crimes. I was guilty as hell, which I think everyone else in the room was. Most were for speeding (and if memory serves, the average infraction was at least 20 miles over the limit). We had a few red light violations. One kid who looked and sounded like Jeff Spicoli confessed not only to being caught speeding, but to not quite remembering just how fast he was going because he was "sort of, you know, stoned at the time."

We all laughed, including the "teacher."

But one of the guilty that day was a middle-aged black man; from his accent, a Nigerian I would guess. When it was his turn, his crime was driving 40 in a 35 mph zone on Alma Street in Palo Alto. Now, at the time, I worked in downtown Palo Alto, an upscale town filled to the brim with limousine liberals, so I drove on that stretch of road virtually every day on my way to and from work. If I did 40 on the road, I would be passed by just about everyone, police cruisers included.

All of us in the room looked at each other sheepishly, because we instinctively knew that he had gotten a black guy driving in Palo Alto ticket.

The bottom line is this - the term "law enforcement" has always struck me as a bit of a misnomer. There is no amount of policing that can "enforce" law upon a society that is unwilling to accept the law. Period. Paragraph. The police are not an occupying force. They should not be seen as one, and they ought not to see themselves in that way.

In order for people to respect the laws, those enforcing the laws must be respectable.

I know people who are cops. I have friends who are in law enforcement. It's an incredibly difficult job. If I am being totally honest, it's a line of work that I lack the physical courage from engaging in because I know that it's dangerous and largely thankless. I live in San Francisco, and I see, everyday, police officers dealing with shit that I - and I suspect that if you're reading this - you would never accept to have to put up with. Police are, as the saying goes, a thin blue line behind which those of us who obey the laws reside behind and rely upon.

And I understand that a lot of the problems cops are forced to deal with is due to the reality that our "leaders" - either because of incompetence, venality, or just a denial of reality - have allowed social problems to fester because it's easier to pander and to mug for the cameras than it is to address real problems. So the cops get to pick up the broken pieces of a broken society that our leaders, and we, have broken.

But that's the job. The job of an officer is to serve and protect. And when one of the officers colours outside the lines, he needs to be held to account. For too long, that's not happened. Derek Chauvin had been reported 18 times in the past 20 years for abuse of power. The leadership in his city did literally nothing about it. The mayor of Minneapolis. The DA. The governor of Minnesota. Nobody acted.

And so here we are, with another man killed by police, and still others killed by violence in our streets.

Qui custodiet ipsos custodes - who will guard the guards?

Again, I have long harboured libertarian tendencies; I despise state-sanctioned abuse of power. I have no interest in preening for social media, to get "likes" from "woke" friends and acquaintances. Long ago, I stopped caring much about what people think, and ceased seeking approval. I simply think that the state has awesome powers, and that it is all too easy to go beyond what is 'just.' I think that it is important to say that the power to enforce the law is too frequently confused with the power to abuse it.

I hate to say it, but it's down to the officers themselves to hold one another to a higher standard of professionalism. I *get* that maybe it's one bad apple in the barrel, but this particular barrel cannot afford to have any bad apples in it.

Models, Models Everywhere

Another post today that deals to a degree in arcanum. The latest iteration of the now famous models of the outbreak of SARS-CoV-2 and its travelling companion, COVID-19. The Institute for Health Metrics and Evaluation (IHME) have been producing models for some weeks now; models which are updated about every three days or so.

As noted, the model uses empirical data sourced from a number of locations to fit (by force) a sigmoidal function called the "Gaussian Error Function" (a sort of fancy way of looking at likelihoods that a variable drawn from a bell curve will fall within a given range).

Though most of the popular press focus on just one result - the projected total number of deaths - in reality the model offers mortality as well as resource utilisation. The latter focuses on items critical to health care - the number of people who will land in hospital, the number who will land in the ICU, and how many will require mechanical ventilation.

The results of the prior iteration for the US were that, by August, just over 65,000 Americans would lose their lives, with the peak on the 15th of April. That represented a reduction from just over 68,000 last week. The latest projection is now up, slightly, to 65.976.

The model must be re-fitted with new data as they become available.

People are to a degree, missing that models of this sort are not true epidemiological tools, as they have more often than not, been deployed to project resource needs. And in this case, what (and when) will the greatest demand be for the critical medical resources be. 

Of course, this approach (forced curve-fitting) is only one approach, and the IHME model has come under some criticism (I honestly suspect, some is motivated by politics, as this is the tool that Dr Deborah Birx and the US Coronavirus Task Force are using).

There are broadly three types of models that are commonly used in this field. These are the parametric "SEIR" models (making estimates across populations based upon the number of people who are susceptible - not yet infected but who could be, exposed - those who are exposed, but not yet positive, infected, and removed - those no longer at risk or ill because they either have recovered, or are dead), agent-based models (in a nut-shell, simulations not unlike the old game Sim City, where a population is created with an initial number of infected people, where the transmission can occur if an infected and uninfected person encounter one another, and then the populations are followed over time until resolution), and curve-fitting models (of the sort the IHME is).

In my career working as an epidemiologist and statistician, I have worked with all three types. (To be more precise, SEIR actually has as a subgroup, SIR, where "exposed" people are collapsed and distributed into the population). Each has its strengths and weaknesses. All require assumptions to be made. 

Most recently, I worked on a team modelling the impact of the introduction of pre-exposure prophylaxis in HIV. We used an agent-based model largely because we simply lacked the right amount of information about movement from compartments in an SEIR model, and thought that the agent-based approach allowed for better hedging against some of the assumptions, as well as being easier to test the assumptions through what in mathematics is called probabilistic sensitivity analysis, or PSA - re-running thousands of mini simulations where the assumptions, rather than being held fixed, themselves are allowed to be drawn from a random distribution.

While I agree with, e.g., Dr Marc Lipsitch (who is one of the world's leading epidemiologists at Yale) that curve-fitting models of this type are unorthodox in epidemiology, I think it's a useful tool.

A lot of hype surrounded the initial projections of the Imperial College in London (a group I, personally, have worked with in the past) that somewhere north of 2 million would die without mitigation. That projection was derived from an SEIR model. Of course, the US has deployed a series of increasingly strict shelter in place initiatives, and that projection almost surely is going to be "wrong" by an order of magnitude.

Statistician George Box once observed, decades ago, that all models are wrong, but some models are useful.

All of the competing models are going to be "wrong" in the end. But what use do they provide now?

First, they give us some parameters on where the pandemic is going. It's not certainty - pace Box - but the projections give us some space to work with. And most provide, in addition to the projections, confidence intervals (or credible intervals) that give a range of what is likely to happen. The less certainty, the wider the bands. 

When reading the projections, you ignore these bands at your peril.

I don't want to weigh in on which is "right," because frankly, they are all going to be wrong. Paraphrasing Tolstoy, while projections that are right are right in the same way, wrong models are wrong in their own way.

Here is a sampling of a few competing approaches.

Columbia University in New York have built an SEIR model to estimate mortality and ICU usage under differing scenarios of mitigation. Estimates ranged from 6800 (with extreme social distancing) up to over 400,000 under strong mitigation. 

Northeastern University have produced an agent-based model here that offers a few scenarios for 'stay at home' mitigation. Its most recent projections are that, by mid-May, approximately 70,000 people will lose their lives. The uncertainty range is 42,000 to as many as 127,000.

Unfortunately, they do not project beyond then, but given the rate of decline of the curves, barring a second flare up, the final mortality is going to be around that number.

A late entry is from a team at MIT, who have an unorthodox approach similar to an SEIR model, but that does not presume priors for initial transmission risk (the famous Ro), but "learns" from the data. That, and other key parameters.

This model is something of an outlier, in two ways. First, while other approaches cease projecting past the "first wave," which is estimated to be more or less over between late June and early July (even for the MIT model), the data scientists at MIT incorporate a second wave - one that will begin to grow in about middle July. 

This echo will add about 25 to 30,000 deaths. It could result in as many as 280,000 when the dust settles.

The first wave is projected, as of now, to kill 104,000 or so by the end of June. The range here is anywhere from 70,000 to 170,000. This is a large outlier from the others.

What then, are the take-aways?

My own preference is agent-based, for no particular reason other than familiarity. The lone agent-based simulation pegs mortality at around 70,000 in the first wave. The team did not project a second, which isn't to say that there won't be one.

The IHME model is now projecting about 66,000 (range or 45-125,000), which is, if not the same as the Northeastern model, in the same neighbourhood. 

One piece of good news is that the models, with the exception of MITs AI model, are converging around similar stories. The fact that the models, using different presumptions and different approaches, net out to a similar result at this stage (we are still three months from July), is a sort of empirical validation.

And it looks like, as of now, mortality is more than likely going to land somewhere between 60,000 and maybe 100,000 at the top end. 

It could be worse, of course. It could be much worse.

The second thing to glean is that social distancing and mitigation are working. All models are converging down, not up, with additional data. The sacrifices we are making are actually, as of now, writing a very different - and brighter - narrative than the story as it was unfolding a few weeks ago.

Keep staying home. Keep distancing yourself. Keep good hygiene.

It's working.

Finally, as the MIT model indicates, we need to be especially vigilant in the later summer. If there is a second wave - and there is every reason to believe that one could come, it is going to be absolutely essential that our public health professionals keep a damned close eye.

And it means our political leaders need to be ready to sound the alarm if there is even a whiff of an outbreak.

And it means we as citizens need to listen - and we need to obey - when we are asked to observe stay at home orders, and not go to the hair salon. It's that simple.

Treatments are coming. Vaccines are coming. It will not be tomorrow.

Again, it's worth saying, by our actions, we are choosing our own future. 

Keep on Keeping On - Day 24

The outbreak of SARS-CoV-2 (the coronavirus) continues. It's a pandemic, which means, of course, that it now is just about everywhere.

As I've said a few times now, I am an epidemiologist, which means that my work focuses on public health. I've spent most of my professional life creating and abstracting information from models.

The president last week warned Americans that the coming days were going to be very difficult, and that admonition has not been wrong.

The news, while terrible, is not completely bleak.

I am following a number of analytical sources each day, trying my best to understand the evolution of the crisis. Two in particular are, I find useful.

The first - the COVID Tracking Project - is provided by a group of journalists, initially led by Robinson Meyer and Alexis Madrigal at The Atlantic. It tracks state-by-state reported statistics on total tests done, how many are positive, how many are negative, how many tests remain to be resolved (results confirmed and reported), how many patients are hospitalized, and how many people have died.

The former are critical from an epidemiology perspective, as we get a feel for the cumulative impact, and importantly, the day over day change. We hear a lot about "bending the curve." For this, the rate of change is a key metric; at least as much as the cumulative impact. The cumulative impact details the past - something we cannot change. The rate of change is more immediate, and can be impacted by choices that we make today.

The latter is important because tracking hospitalization gives us a much deeper view into how the disease is actually manifesting. As is now well-known, about half or so of people who get infected are either totally without symptoms, or have mild to moderate symptoms. They don't require hospital, and overwhelmingly will recover. For these people, COVID-19 will be an unpleasant experience. It won't be a fatal one. The more severe cases - ones that require hospitalization, or worse, ICU admission - are the ones that really drive the magnitude of the fear. These are virtually all of the patients who will die. They are the ones who will compete for resources.

I recommend to bookmark and check their data each day.

The second is a project run by the Institute for Health Metrics and Evaluation (IHME), a research centre at the University of Washington in Seattle. As an aside, I know, personally, more than one person at the University of Washington Department of Biostatistics, and it is one of the best in the world.

This team uses reported data on infections, mortality (death), hospital admissions, ICU admission, and ventilator demand to model the trajectory of disease. Data at one point were updated nearly daily. Updates now are regular, but not quite at the level.

This is one of the models the US government looks at when making decisions on resource planning, and it is the one that Dr Deborah Birx often refers to in the daily press briefings.

Like the COVIDtracking group, the IHME estimate, on a state by state basis, current predicted hospital loads and mortality. But they go a level deeper - projections are made on admissions to ICU and itubations (need for mechanical ventilation). The latter two are critical to understand the ability for our health care systems to meet life-saving demands of the infected population.

Predictions on mortality are also offered.

You can go to the site and see how your state is "doing" with respect to mortality and demand vs. resource needs.

Initially, the model predicted that mortality in the US would grow, slowly at first, then rapidly (a classic exponential growth model) until mid to late April, plateauing, and then falling until about June. When the statistical dust settled, it forecast around 100,000 deaths in the country, with a range of 75,000 to 250,000.

Those are terrible numbers.

About 95% of the country is now under direction to observe "social distancing" - an awkward phrase that really just means "separate yourself, physically, by about six feet from other people." It means to stay home unless essential - going to the grocery store, for example. And it means being vigilant about hand washing.

The results are starting to come in.

Friday, the predicted mortality of the US from this forecast model was about 95,000.

Monday, when updates were available, that number had fallen to 81,000.

The latest news this morning puts the estimated number at just over 60,000.

That's a lot of people. But it's a third less than the initial estimates.

Actions taken by people are starting to show results. The mortality curve is flattening. Here is how it looks as of today:

The coloured range should get your attention - this is a band of uncertainty (remember; these are mathematical models). The current situation has a range of about 40,000 to as much as 130,000 dead. The total mortality could turn out to be 130,000, even given where we are now.

These are, it's worth noting, models. As Dr Fauci noted, models have utility, but data are better. Statistician George Box famously quipped that all models are wrong, but some are useful. For me, this model is quite useful.

You'll also note that the line is solid until today - this is the historical data. The dotted line are projections. If that solid line trends back up, projected mortality is going to go up even more.

I re-iterate the point I've made a dozen times.

HOW this plays out is up to you. It's your choice. It's your future.

The final narrative is ours - whether it's a scary and terrible chapter, or a catastrophe.

These data are a hopeful sign. But they also should be a warning.

Stay home.

A Few Questions (and Answers, I Hope) about Hydroxychloriquine

Apologies for what is likely to be a very, very dry post today. We are living in strange days; better ones are coming. The comments to follow are not political. They should not be seen as endorsing one political narrative versus another.

As Queen Elizabeth (channeling Vera Lynn circa 1939), we will meet again.

CAVEAT: I am not a medical doctor. I am an epidemiologist. It is (and has been, for 26 years) my day to day job to build, run, and abstract the results from disease models. I've run analytics of randomized clinical trials. I have helped prepare (and been a subject matter expert for questions from) the United States Food and Drug Administration (FDA).

But I am not a "scientist." I would not question the medical expertise of a doctor, whose job it is to make medical decisions.

Let me say, with no ambiguity or equivocation, that ANY decision (yes or no) people make about medical care absolutely should be made in consultation with a doctor.

In the past few days, there has been a lot of talk in the news and the popular press about the use of hydroxychloroquine (with or without azithromycin) to treat people suffering from infection with the SARS-CoV-2 virus. The US president has made many statements in support of it. People in the press have attacked his comments.

There is, I think, a lot of misinformation and misunderstanding about these medicines, why there is some belief that they help treat COVID-19 (the illness associated with SARS-CoV-2), the risks of the medications, and frankly, what is going on.

What is COVID-19? 

First, you hear "COVID-19," "coronavirus," and, to a lesser extent, "SARS-Cov-2" used interchangeably. They aren't.

COVID-19 is a terminology resulting from the abbreviation resulting from "coronavirus disease" (COVID), concatenated with 19, the year (2019) it was identified. This is a standard way that the World Health Organisation (whose job it is to come up with the nomenclature) assign.

Coronavirus is a heuristic to describe a family of viruses (of which this particular strain is included) that are so called due to their physical structure - a central structure that houses the RNA (essentially, viruses are primitive structures of genetic material) with spiky projections that make the virus look like a crown. The word "corona" means "crown," in the original Latin.

SARS-CoV-2 is an abbreviation for "SARS-CoV" (severe, acute respiratory syndrome, of the coronavirus type). It is a strongly believed to be a close genetic cousin of the virus that caused the outbreak of SARS in 2005, hence the "2." The name was implemented by the International Committee on the Taxonomy of Viruses.

So briefly, the virus is SARS-CoV-2; the illness it provokes is COVID-19. Think of it in parallel that HIV is the virus that causes people to get sick. AIDS was the disease that resulted. It's not a perfect metaphor (and thankfully, with highly effective treatment, these days, people with HIV infection can suppress infection and avoid AIDS).

What is hydroxychloroquine?

Hydroxychlorquine is a medication that was first approved for use by the FDA in 1955. It is in the family of antimalarial drugs called aminoquinolines. Its first use was for treating malaria; later, it was approved by FDA for use in treating Lupus (SLE), and rheumatoid arthritis. Its activity against infection was well-established in its early days against malaria. How, exactly, it works with RA is still not well understood.

Hydroxychloroquine is known under a brand name called "Plaquenil."

It is on the WHO List of Essential Medicines - a list of what the WHO describes as the safest and most effective medications that are essential to basic health for a health system. These represent well-established and basic for the key population health needs. There are currently approximately 500 medications on this list.

What is azithromycin?

Azithromycin is an antibiotic (medications that are used to kill bacterial infections) called a macrolide antibiotic. It has broad activity against a host of GRAM positive (and some, more serious GRAM negative) bacteria, and is widely used for inner ear infections, community acquired bacterial pneumonia, skin infections, and some respiratory and throat infections. It was first approved for use in the USA in 1988.

Azihtromycin is marketed under the brand name Zithromax; often, it is sold in seven or 10 days packages called "Z Pack."

Azithromycin is, like hydroxychoroquine, on the WHO list of essential medications.

Why has hydroxychloroquine been suggested for COVI-19?
There are several problems with Dr Raoult's study. The first is that the sample size is very small. Only 42 patients is too small a sample for any regulatory body to approve a medication for use.

The results are encouraging.

One of the controversies not said in the US media is that Dr Raoult is not without controversy. He is a highly respected infectious disease doctors. He was named one of the ten leading researchers in all of France by Nature magazine, and has published two thousand peer-reviewed manuscripts in his career. He was awarded, in 2010, with the Grand Prix de l'INSERM (Institut National de la Sante et de la Receherce Medicale), the French national institute for health research.

ALL medications have adverse events. When FDA approve drugs, it is implicitly understood that there are risks. When medicines are approved, FDA (and other regulators) are asked to balance the risk/benefit calculus - is the benefit that the medication greater than the risk associated?

Frequent complaints on the news are about how the use of hydroxychloroqine as an intervention represents bad, or at the least incomplete, science. Dr Anthony Fauci, who, with Dr Deborah Birx, are the medical experts informing our government's response to the outbreak of SARS-CoV-2. Dr Fauci is one of the leading experts in the country on infectious disease. He earned his bona fides over the years working in HIV disease, as did Dr Birx. His opinion absolutely must be respected.

Medications are "approved" for use by regulators - in the US, by the FDA. When they are approved, there is a very detailed "label," and more in what is called a package insert - the little paper in six point Courier type in the bottle - that describe the indication (the disease its use is "approved" for), side effects observed by more than 1% of patients in the trial, the clinical trial data, dosing, and other details.

COVID-19 is a very serious problem. As of this writing, 400,000 Americans have been diagnosed. 13,000 have lost their lives.

A small, observational study was conducted by the French infectious disease expert called Didier Raoult at his hospital in Marseille, France (Institut Hospitalo-Universitaire, or IHU) in which he treated 42 patients who had been admitted to his hospital with COVID-19, at various severity of disease. 26 of the patients received hydroxychloroqine. 16 received 'standard of care,' which is to say, palliative care. Six of the 26 in the treatment arm had azihtromycin added to their treatment.

The results were published by Dr Raoult in the International Journal of Antimicrobial Agents in mid-March 2020.

Dr Raoult reported that 14/20 (70%) of the treatment arm were reported free of viral loads at six days following inclusion. In the control arm, just two had this outcome (12.5%).

This is a stark result, and is certainly, from the perspective of statistics, an encouraging number.

So, what is the controversy?

Second, the study was not a 'randomised control trial' (RCT). This is the gold-standard for the research and approval of medications in the US (FDA), the EU (European Medicines Agency, or EMA), Canada (Health Canada), and most other industrialised nations on earth. It involves "double blinding" (enrolling patients into the trial into arms that neither the subject nor the investigator knows is which) that are broken only at the end to control for biases. Dr Raoult's study was "open label" (subjects and doctors knew who was in the treatment arm, and who was in the control arm), and it was observational (meaning that there was no attempt, through randomisation, to allocate patients into the two arms to balance things like underlying health, age, and other factors that can bias results).

Third (and in my view an under-reported problem) is that the study was not an intent to treat (or modified intent to tread) analysis. Dr Raoult reported that 14/20 patients (and 6/6 of those on both hydroxychloroquine AND azithromycin) recovered. In fact, there were six patients lost to follow up, and not included in the calculations. Three of these in fact died (of their infection, not side effects). Three others did not complete treatment. So the results reported (70% efficacy) represent a sort of survivor bias. In fact, 14/26 (54%) recovered. That's much less exciting than the numbers broadcast.

The study in effect was very small, uncontrolled, and had design issues. People are right to be sceptical of these results.

Who is Dr Raoult

A significant part of the backstory that frequently remains unsaid in the US media is that Dr Raoult is not without controversy. He is a highly respected infectious disease doctors. He was named one of the ten leading researchers in all of France by Nature magazine, and has published two thousand peer-reviewed manuscripts in his career. He was awarded, in 2010, with the Grand Prix de l'INSERM (Institut National de la Sante et de la Receherce Medicale), the French national institute for health research.

He is, in short, an acclaimed doctor and researcher.

But he is idiosyncratic. In 2013, he ventured outside his lane and questioned climate change, which drew widespread ire and scorn.

What role is there in the arguments about safety?

Both hydroxychloroquine and azithromycin are among the most prescribed medications in the world. If you are over the age of five, it is almost certain that you have taken azithromycin at some point. Of course it has risks - the most significant, perhaps, is that it causes QT prolongation - a heart condition that can result in irregular heartbeat. This is a real, but rare risk.

It is not zero.

The reality is, most of the "side effects" of the treatment are things like nausea, rash, and headache. These are the types of common 'adverse events' reported in most clinical trials. Anecdotally, of the trials I have run analyses on, nausea, headache, diarrhoea, and rash have in every case been the most common events reported.

What about the 'science?'

But people, I think, are either misunderstanding what Dr Fauci is saying, or they are distorting it.

He is a scientist as well as a doctor. His comments reflect that the only way, really, to establish the efficacy of a treatment right now is via RCTs. Randomisation is simply the best way to mitigate sampling and other biases. Using control arms are the best way to establish placebo effects.

In a perfect world, of course we would conduct multiple RCTs. And I suspect that we will. Many are right now going on, and the results will be in.

The problem is, we simply do not have the luxury of time.

I am old enough to remember life before the advent of effective HIV therapies (in fact, not that long ago). 25 years ago, when antiretroviral therapies (ARV) had not been discovered, the criticisms of FDA among others were that they were too slow to react and were obstructing treatments.

HIV activists were, at the time, highly critical of Dr Fauci for just this reason.

Dr Fauci's is right to be conservative. It is part of his job to question whether this approach will work.

But people need to listen to what he is actually saying rather than what they think he is.

Basically, the treatments have side effects, but they have been in use for decades, and are on the whole, pretty safe. They don't have no risk, but the risks are well-known. What we don't know is the actual efficacy, which the RCTs will establish.

Thus, in deciding whether or not to treat, patients should consult their doctors; medical expertise should decide.

In short, talk with your doctor.

Both hydroxychloroqine and azithromycin require a doctor's prescription. You cannot walk into Safeway and pick it up as if it were aspirin.

What does it mean for a drug to be "approved?" What is off-label use?

Medications are not "approved." They are approved for specific diseases. Adalimumab (Humira), for example, is "approved" for rheumatoid arthritis, psoriasis, ulcerative colitis, and a few other autoimmune disorders.

Doctors can - and frequently do - prescribe medications for disease not specifically indicated in the label. This is called "off label use."

The laws of the US presume that the best person to decide care for a patient is his or her doctor - a medical expert who knows the specifics of the patient before him or her - and is best positioned to understand the nuances, risks, and benefits to make the best medical decision.

This is, again, why it is critical for patients to talk to - and listen to - the opinions of their doctors.

Right now, you cannot get access to hydroxychloroquine - whether for an approved use (Lupus) or off-label (COVID-19) without your doctor.

Bottom Line

The reality is, those numbers are going to end up being much higher.

I don't know that hydroxychloroquine (with or without azithromycin) is effective. The initial evidence is encouraging, but it remains to be seen if this will be borne out in larger studies.

I do know that both have some risks, but those risks are pretty small. The risk of death from SARS-CoV-2 is many orders of magnitude higher.

We hear, every day, about ventilators. And it's true that they are essential. Without them, virtually all of those who require invasive ventilation would die.

But they are not a cure. Data right now indicate that, of those going in ventilators, mortality is 30-50%.

I worked, 10 years ago, in Phase II (dose-ranging) studies for a novel treatment of Lupus. One of the comparators we used was Plaquenil. Safety for Plaquenil was something we evaluated versus our treatment. But it was not the driving factor. Not close.

If I were to test positive for the virus, I personally would not immediately turn to this unproven therapy. But if I were to be put in the hospital, I would seriously talk to my doctor about it. And I would absolutely listen to what the doctor said.

The claims by the president that "you have nothing to lose" by trying hydroxychoroquibe are false.

But given that we have nothing else in the armamentarium right now means that I would think long and hard about the novel treatments before I required a ventilator.

Just Do It

Seventy six years ago, in the early hours of an early spring morning, young men from the various allied nations loaded themselves into a series of sequentially numbered metal delivery vessels off the southern coast of England. The ask of them was not complex, but it was difficult.

The potential future of the world depended in no small part in their execution of that ask.

It was simple, but it was not easy. Many knew that they would not even make it to the dry land. But they went.

When asked, they responded.

As a people, no-one in my generation, or those above or below us, has seen a moment quite like that.

Our moment is here.

There is another enemy, but it doesn't wear spit-shined boots. It does not confront us with Panzers or Messerchmitts or Junkers. It is not led by an evil man with bent symbols and a toothbrush moustache.

As of this moment, according to data being tracked here by the Johns Hopkins University, more than three quarters of a million people in the world have contracted the SARS-CoV-2 virus (COVID-19). In the US, we now have 164,000 confirmed cases.

Both numbers are likely an order of magnitude wrong at this point.

We've all seen the images from Italy. Many have seen the devastating numbers in Spain.

Six years ago, during the last viral outbreak (Ebola, at the time), I wrote this about the treats our ancient enemies (viruses and bacteria) present:

There has been a number of movies and books with doomsday stories.  In order of decreasing likelihood, the list includes asteroids crashing into the earth.  Widespread terrorist attacks,  nuclear war.  zombie apocalypse.  The first is a virtual certainty given sufficient time; the last is, despite an actual epidemiological simulation run at a reputable university in Canada, not ever going to happen outside the imagination of George A. Romero or Rick Grimes.  I am not particularly concerned about any of these.  But one thing I do actually have on my fear radar is a viral or bacteriological plague.  

In short, we are overdue - WAY overdue - for a thinning of the herd, so to speak.  The last really great plague was the so-called Spanish Influenza of the early 20th century.  What? No.  SARS does not count.  In 1918, the flu infected nearly a half billion people, killing around 20% of them.  100 million dead is a lot of people just on its face.  But considering that the world population then was only about two billion, the Spanish Influenza killed around one out of every 20 people on earth.

• Stay home.
• Wash your hands.
• Avoid unnecessary travel.

This is not a drill.

SARS-CoV-2 is not likely to be the Spanish flu (and we should be on our hands and knees being thankful for this); but we need to take this seriously.

I repeat - if the epidemiology from 1918 plays out here today, more than one hundred million people around the world are going to die in the next 18 months.

This does not need to be our future.

We are not merely ships tossed on a tumultuous sea of fate and fortune.

Here in California, our governor ordered a state-wide "shelter in place" more than two weeks ago. He made it clear why this was so. And he reminds us, daily, that our future is in our hands.

Like the soldiers who hit the beaches of Normandy in 1944, we have been called. The ask of us, like them, is not complex.

We aren't being asked to load into troop transports pre-dawn. We are not asked to face enemy fire. We are not asked to storm dug-in positions on a beach in a faraway land.

We are asked essentially to do nothing.

And unlike those soldiers, if we follow orders, most of us are going to come out unharmed.

Our moment. Our choice. Our future.

Here is a simple breakdown of the course of disease, from initial infection to resolution.

For most of us, SARS-CoV-2 represents a fairly mild problem. 85 per cent of us fall into the top two cohorts. Most who are infected will have no (30%) or mild to moderate (55%) symptoms.

A small number (10%) will have severe symptoms, and will require hospitalisation.

Fewer still will have critical symptoms.

ALL of those who are infected will have a period where we are contagious. Even those who have no symptoms at all will, for about three weeks, be able to infect other people.

Critically, those in the 5 and 10 per cent cohorts.

And here is the rub. Of those who land in the critical cohort, current data are that fully half will die. In the severe cohort, estimates are that 15% (one in about six) are also going to die.

These two skew heavily into groups who are older (over 60) and/or those who have other underlying conditions. Asthma. Diabetes. Immuno-compromise.

Many people are discovering that they have "underlying conditions" after they are diagnosed with COVID-19.

But you are going to know someone who does.

By these estimates, crudely, if half the critical cohort (5% of the population) and 1/6 of the severe cohort (10%) are at risk of death, that's about four per cent of the population.

SOMEONE you care about is in that group.

Let me put that another way.

Think of twenty people that you know. Your mother. Your uncle. Your sister. Your daughter. A teacher you're fond of from when you were young.

If this model holds true, one of them is not going to be alive in a year if you don't stay home.

Maybe you're young. Maybe you're healthy. Chances are pretty good that you're not going to get terribly sick.


Do you have someone in your life that you want to nominate to be taken away by this? I don't.

The movie does not have to end this way. There is no need to panic; there is absolutely a need to act.

Stay home. Wash your hands. Avoid unnecessary travel.

Our moment. Our choice. Our future.

Please stay home.

Like Clockwork

Today is one that's been on the calendar for a long time. In truth, since calendars were made of course, but from my own personal calendar, since 2000.

One of the advantages of being born in a zero year (I was born in 1970) is that the maths for the milestone years are a bit easier.

As a result, in the year 2000, I turned 30 years old. While the rest of the world was exhaling from the fact that we achieved the year without the computers simultaneously exploding and taking the developed world with them, I woke that day 20 years ago to the idea that I was finally, officially, a bona fide adult.

I've written a couple of times on the topic, but I clearly remember that birthday. My mother was visiting me in my home (in those days) in San Jose, California. The day began with some showers, but the sun came out. We spent lunch at Valley Fair Mall (now "Westfield Shoppingtown") where we grabbed a quick meal and a tiffany lamp for the house. On the way home, we stopped at the San Jose Municipal Rose Garden (which was one of my favourite spots in the city) before returning for dinner. Even at 30, it was a nice treat to have my mother prepare my favourite meal for a birthday.

I remember thinking that 30 was a milestone because I know longer thought of myself (or referred to my friends as) a "kid." All the trappings of adulthood of course existed already - real job, dog, house and mortgage. I had done my taxes already several times. I had a retirement fund. But now, there was no going back.

After all, 30 was the age when people in the 1970s cult film "Logan's Run" faced the final curtain.

But I also thought of the reality that at some point, I was actually going to be 40. And then 50. 40 came and went a decade ago.

50 arrived today.

Those who know me are already aware that my hobby is my 1952 MG. It's not "modern" in any way - 54 BHp engine, no power steering, no top. All its workings are mechanical.

I got the car for my 40th birthday, and from time to time, I am in the garage working on this or that 'thing' that decides in its uniquely British way that it just no longer wants to work properly.

The car was already 18 years old when I was born.

In the past decade, certain parts have just...worn out.

About 8 years ago, one of the carburettors developed a hairline crack, so it had to be replaced. It took a while, but I found a spare in Oxfordshire, England - ironically just a few miles from Abingdon, where the car was made. The factory was closed in 1980 or so, and now, a Starbuck's is where the cars used to roll off of the assembly line.

A carburettor is a device that used to exist in cars that more or less functions the way that your lungs do. Gasoline - the life's blood of an internal combustion engine - is mixed with air before being sucked into the ignition chamber, where the two are combined with a spark to drive the piston, and then, the car itself. If the carbs leak air, or are out of balance, your car will gasp in much the same way that you will if your lungs aren't working.

Two years ago, the starter's solenoid needed replacement. That was an easier "find" - an OEM still manufactures Lucas knock-offs online. A week later, the old one was out and the new, in. Back on the road.

In time, I've also replaced the dynamo, an oil line, and an odometer cable.

A 70 year old car has 70 year old parts that fail. But those parts can be replaced. So it will remain on the road as long as I have the interest in keeping it going (and the physical ability to do so). At some point, I hope that my son (now 14) will be interested in it, and I can give it to him. When he was six or so years old, he "helped" me replace the broken carb.

A human being is in one sense, a collection of parts. Some can be replaced easily, some not so easily. One of other off-time activities is running. 11 years ago, I wrote a brief blurb about it here.

In 1998, I was able to run 2000 km in a year. At the time, I could pretty easily keep a seven minute per mile pace. Pushing it was 40 minutes for a 10km (about 6.30 per mile).

At 40, I could keep a seven minute per mile pace, but it was not easy.

Age and wear and tear slow you down.

Last year (2019), I was able to log about 500 miles total And my goal is now eight minutes per mile. I get the occasional leg injury (pain in the heel of my foot, a strained gastrocnemius). These injuries take much longer to recover than they did. A tweak used to put me on the shelf for a week, maybe two. This past fall, leg tightness meant reduced activity for two months.

Unlike the car, I cannot go out and get a new lung, or replace a leg. Joints can be replaced with titanium, but they honestly aren't the same.

I used to laugh when my father would fall asleep in our green armchair in the living room after dinner. Last night, I was sitting on our sofa and briefly nodded off. Dad was 53 when he died, so he never was really an old man, even though I thought of him as one for most of our shared time.

Today, I'm fifty years old. And despite the fact that my own parts don't work as well as they used to, I am ok with it.