Saturday, April 11, 2020

Coronavirus: mortality rates, hidden information, withheld drugs. Part 1

1.  Coronavirus by the numbers

Today, the United States has over half a million people who have tested positive for Coronavirus.  

Today, the United States became the nation with the highest death toll in the world from the novel coronavirus.  Twenty thousand US deaths.  In the space of 6 weeks we have gone from zero to 2,000 deaths per day.  Yet most of our country has yet to experience the wrath of this virus.  My county has only 4 known cases, and my state has had only 17 deaths... so far.

After exposure to the coronavirus, it takes on average 5-6 days, but sometimes up to 2 weeks, to become ill.  Then, if you are one of the unlucky 20% who become seriously ill, in another week you may crash with respiratory failure.  It takes about another two weeks for roughly half of the seriously ill to die.

Death rates therefore trail exposure by about a month.  Case rates will trail exposure by 1-2 weeks.  We have been quarantining ourselves to a degree for 4 weeks now. Case rates and deaths should be leveling off, and they appear to be.  That horrifying exponential curve, in which deaths were doubling every 2-3 days, has begun to flatten. This is good, but it is just the first step in dealing with the emergency this virus created.  Quarantining the public last month was the only possible plan A to minimize deaths.  But it seems our leaders have no Plan B to return us to normality.  More on this in Part 2.

The novel Coronavirus (its official name is SARS-CoV-2) is the newer and nastier version of its 2003 cousin, SARS-CoV:  they have the same 11% mortality rate, the same high environmental stability, but the new coronavirus is much more infectious.  Let me repeat that:  the current pandemic is the second iteration of SARS, and this virus has the same official name as SARS, except that a 2 has been added to indicate it is #2.

Both SARS-1 and SARS-2 have an incubation period of about 6 days, and an Rzero estimate about 2.7, which is the number of people each person with the disease is likely to infect.  Each virus causes pneumonia, but can also infect the gastrointestinal tract and the upper respiratory tract.  Each frequently induces a cytokine storm and ARDS.  SARS-2 has been noted to cause myocarditis and heart failure. 

2.  What about those mortality rates?

According to one of the excellent SARS-2 tracking websites, the SARS-2 mortality rate is 7%, calculated by the number of people in the world who tested positive (the denominator), and the number who have died from SARS-2 (the numerator).  The first problem with this method is that most cases were diagnosed recently, and have not had the illness long enough for us to know whether they will survive or succumb.  Looking at the US alone, using this same method of calculation, the US mortality rate is 3.75%.  But especially in the US, most cases were only recently diagnosed. The other problems with this method are a) that testing has been limited, reducing the potential number of identified cases, and b) that multiple tests are being used, some without prior FDA review, and their sensitivity and specificity are unknown.  Various tests are being used in the rest of the world, with some countries performing widespread testing and others restricting testing.

Given those caveats, let's look at 4 European countries where the pandemic spread earlier than in the US, and are therefore farther along the epidemic curve. Theoretically, their mortality rates will be more accurate. Using the identical method as above, one calculates a mortality rate for Italy of 12.8%.  Spain's rate is 10.2%.  France's rate is 10.6%.  The UK's mortality rate is 12.5%.

3.  New York, our harbinger

If you zero in on New York, our worst-hit state, at first glance it does not seem too awful.  Total positive tests: 170,512 and total deaths 7,844, for a 4.6% mortality rate.  

How many people required hospitalization?  33,159 cumulatively, with 18,569 currently hospitalized.  The recovered are said to total 14,590.  Coronavirus cases in New York currently fill about 1/3 of the 53,000 hospital beds NY had at baseline, although they fill a disproportionate number of ICU beds.  Of those hospitalized in NY, 27% are in ICUs.

If you compare the number who have died to the sum of the recovered (discharged from hospital) plus the deceased, the numbers (and the benefits from treatment) do not look very good:  30% of those who were hospitalized for coronavirus died, while 70% recovered.  If 20% of those with coronavirus require hospitalization, as claimed, and 30% of those hospitalized die, and no one died at home, there would be a mortality rate of 6%.  However, NYC reported a spike in those dying at home.

What does all this mean?  In my opinion, the quality of medical care in western Europe is at least equal to that in the US.  While that assertion is arguable, life expectancy is higher in each European country I presented than in the US.  The NYT this week called France's healthcare system "one of the world's best."

While we ought to benefit from the knowledge gained by those treating this disease first in Asia and then Europe, it does not seem that what we have learned has made much of a dent on the mortality rate.  I anticipate we will see mortality rates equalling those in western Europe over the next few weeks.

From where did Dr. Fauci get his data when he predicted a 1% mortality rate?  Does he have better data that has not been made public? 

4.  Medical mysteries.  Doctors around the world are talking to each other, but strategies to improve survival remain elusive, or restricted

Our world is now 4 months into this pandemic.  Over 100,000 people have died, and hundreds of thousands have been hospitalized. 

How can it be that we know so little about the proper medical management of this disease?  Why isn't information on drug trials available yet?  China reportedly had 260 trials.  Europe has had more.  Many different drugs have been tried.  Where are the data?

How can it be that perhaps two thirds of those who are placed on ventilators do not come off alive

Why are some manufacturers allowed to have a lock on patents and prices, when the cost to manufacture most of the most promising drugs is minimal?

5.  We want drugs now, but they want a vaccine later

How can it be that Dr. Fauci is indignant about using hydroxychloroquine (a drug costing about $1.00 per patient course) on potentially fatal cases because there is "only" anecdotal and lab evidence of success, yet he is thrilled to sponsor a clinical trial of coronavirus vaccine in humans before it has even gone through animal testing, as required by law?  Why does he have such a high evidentiary bar in the first case, and such a low bar in the second? 

Why are the doctors leading the US' coronavirus efforts unable to do more than spout platitudes and pay homage to disease models that fail to include accurate data?  Why do they sound more like politicians than doctors?  Is anyone looking out for the public's health today, rather than going gaga over a vaccine that may or may not be available in a year or two?  And which may or may not actually enhance the disease's virulence in recipients?  According to Nature:

"With SARS-CoV-2 vaccines, researchers’ main safety concern is to avoid a phenomenon called disease enhancement, in which vaccinated people who do get infected develop a more severe form of the disease than people who have never been vaccinated. In studies of an experimental SARS vaccine reported in 2004, vaccinated ferrets developed damaging inflammation in their livers after being infected with the virus."
New vaccines are highly profitable.  Gardasil, Prevnar and the MMRV vaccine each sell for over $200 per dose, and each recipient requires multiple doses.  What might a successful coronavirus vaccine cost?  Does the potential for huge profits from a new vaccine versus the limited profitability of old (and mostly generic) drugs have anything to do with Dr. Fauci's preferences?  Why are the mass media breathless over a corona vaccine, while shouting dire warnings of the dangers of hydroxychloroquine?

6.  Dangerous drugs?

Do you want to discuss truly dangerous drugs?  Consider SSRI antidepressants.  They are associated with a boatload of suicides, such that they are labelled with "black box" warnings, used for only the riskiest drugs.  Yet according to NBC, 12% of Americans take antidepressants, most of which are SSRIs.  They are associated with cardiac toxicity and arrhythmias, especially if taken with certain other drugs.  Are our public health officials using the media to warn us about this major public health risk?  

Chloroquine, and the related drug hydroxychloroquine, are naturally associated with some risk, as are all drugs.  But they have a very interesting benefit:  they kill SARS-2. They may also reduce the excessive inflammatory response that often leads to death.
 They have no "black box" warning and are sold over the counter in many countries.

The FDA approves and labels drugs based on their risks and benefits.  Thus a cancer drug, which may kill you, is approved because the cancer may also kill you, and FDA reasons that a greater level of risk is warranted under the circumstances.

The primary risks of hydroxychloroquine are cardiac arrhythmia (not common, and generally only a problem when there is an interaction with other drugs the patient takes) or ophthalmic toxicity, which occurs almost exclusively with prolonged, cumulative use.  I check drug interactions when I prescribe hydroxychloroquine, and pharmacies do as well.  Used under these conditions it is a very safe drug.  I have prescribed it for lupus, Lyme disease and rheumatoid arthritis, and I took its cousin, chloroquine, for nearly a year for malaria prevention.  

Dr. Oz interviewed rheumatologist Daniel Wallace, MD (a favorite doc of mine for his writings on fibromyalgia) who has treated thousands of patients with hydroxychloroquine.  Dr. Wallace notes that as monotherapy (used alone, so there are no drug interactions), there are no reports in the medical literature of deaths from the drug. And none of his patients taking the drug have developed Covid-19.  At LA's Cedar-Sinai hospital, where he works, only one lupus patient on hydroxychloroquine, who took the drug intermittently,  has been admitted with Covid-19.  

In India, healthcare workers are being given this drug in the hope it will prevent SARS-CoV-2 infection, and India initially banned exports so it would have enough for its own population. The Indian Heart Rhythm Society has issued recommendations for the safe use of hydroxychloroquine. 

Yet Newsweek ran a major story 3 days ago which began:  "Hospital in France has had to stop an experimental treatment using hydroxychloroquine on at least one coronavirus patient after it became a "major risk" to their cardiac health."  Is Newsweek serious?  'At least' one patient had a well known, not unexpected side effect of a drug, in a foreign country, and it makes the headlines.  I hate to tell Newsweek, but Covid-19 causes respiratory failure, heart failure and death. In fact, Covid-19 by itself causes myocarditis and cardiac arrhythmias"
One review of severely ill patients in China found that about 40 percent suffered arrhythmias and 20 percent had some form of cardiac injury."

What happened to that balance between risk and benefit that allows lethal cancer drugs to be sold?

Apparently the deafening warnings about the dangers of hydroxychloroquine and chloroquine failed to stem interest in the drugs.  So restrictions are being put into place to stop physicians from prescribing them, except under very limited circumstances.  The drugs won't be permitted for prevention, and in some cases may only be allowed for hospitalized patients.  This is a very bad idea, because once you are hospitalized, you are already very ill and it may be too late for the drug to have a beneficial effect.  

Australia has restricted chloroquine prescribing by physicians to only those patients who were already on the drug, or only when prescribed by certain specialist physicians.

France restricted its use  to only severely ill Covid-19 patients, then partly loosened prescribing.  Yet until several months ago, chloroquine was an over-the-counter (no prescription needed) drug in France.  That should be ample evidence of the lack of concern French drug safety officials had about the drug.  And chloroquine has more side effects than its cousin hydroxychloroquine, which is currently the preferred drug in the US for Covid-19.

In the US, new guidelines or restrictions on dispensing have been implemented in 23 states, split equally between Democrat and Republican governors, through new rules for pharmacists.  

In response, the American Academy of Physicians and Surgeons, an organization of private physicians, has called for these restrictions to be lifted.  In New Jersey, physicians and legislators have banded together to end the restrictions.

A survey of 1,271 US doctors conducted this week found that 65% would prescribe the drug to their own family members for treatment or prophylaxis. Only 11% would not use the drug at all.

While at first glance it seems reasonable to restrict use of the drugs to avoid shortages, that does not appear to be the issue.  Thirty million tablets have been donated to the US national stockpile by Sandoz, under the condition that liability for injuries is waived.  Teva has donated 16 million pills, and Amneal 20 million.  Bayer, Novartis and Mylan have promised to provide many millions more.  
The recommended course is a total of 12-16 tablets over 5-6 days.

Is restricting prescriptions for chloroquine and hydroxychloroquine protecting the public health or jeopardizing it?  And are those restricting the drug playing doctor without a license?  I'm guessing that President Trump, who called hydroxychloroquine a 'game-changer' and whose administration finessed the donations, has not been informed that the public has been prevented from accessing his favorite drugs. We know that restricting the availability of these drugs was clearly NOT part of the Trump administration's plans. According to Axios, at a meeting one week ago today:

"The principals [of the coronavirus task force] agreed that the administration's public stance should be that the decision to use the drug is between doctors and patients."
And Trump said, according to the same article,
"What do you have to lose? Take it," the president said in a White House briefing on Saturday. "I really think they should take it. But it's their choice. And it's their doctor's choice or the doctors in the hospital. But hydroxychloroquine. Try it, if you'd like."
But that is clearly not what is happening.  Has Dr. Fauci found a way to perform an end run around Trump's wishes?  Who gave the orders to limit the drugs' use?

The story will be continued in Part 2.


olddochall said...

Hoping someday they will let the Doctors, Nurses, Lab Techs, and rest of medical profession practice medicine without politics involved. Let us look out for the health of the population, practice medicine based on valid research not big business and political gain.

Brian said...

Great work as always. I'm just coming back after not having read for a while, but I'm glad you're still writing. I'm one of you long-time readers from 2009 and was doing my double masters at the time in epidemiology and environmental health science.

I'm curious to know your numbers of 30% mortality ratre in NYC. What numbers were you using for deaths (The total deaths in the state?). When I crunched these, I found a 35% mortality rate.

I have been watching the mortality rate in Excel for more than 6 weeks now and while it was rising (up to 70% early this month, though I was discounting those numbers as likely not being generalizable to the public as a whole), it has been falling somewhat nationally.

That being said, it's interesting to me that it fell from 70% to 40% in two days (and while I was on the phone with some docs presenting on Zoom, 4 people magically "undied" and one person "unrecovered" which was quite interesting indeed!!).

Anyway, currently, global mortality rate is hovering around 20% and we are up over 40% again (though with massive testing only starting recently, I'll await more data to see when those numbers really level off.

I'm curious to know have you seen much on the sensitivity and specificity of any of the antibody lab tests being used? I've seen some from China on nasal swabs and throat cultures, but not in the US.

As always, a pleasure to read your work. Now I have to go back and read your stuff from the beginning. :-)

Meryl Nass, M.D. said...

The NY numbers come from here:

There is also a button for the daily stats starting around end Feb, and another for stats by county

The "recovered" is actually hospital discharges, not total recovered patients. Yes, hospital mortality is huge.

Science cited a blood transfusion expert this week who said the nasal swab is 50-70-80% sensitive when just one is done.

I am not sure why antibody tests have taken so long to develop; were past coronavirus colds yielding positive results with the first antibodies chosen?

Meryl Nass, M.D. said...

Here is the Science article. Hi Brian, I remember you!

Brian said...

Thanks, Meryl :-) I'll be here asking questions that I don't have time to go too deep into (work, doctoral program, etc.), but know that you might know.

I appreciate all you do, so thank you :-)