Thoughts on "Wonder drug" combination Hydroxychloroquine and Azithromycin

I (and a lot of other people) was really excited about this paper when it originally was released. It appeared to show that a combination of Hydroxychloroquine (an anti-malarial drug that can slow SARS-CoV-2 growth in a test tube) and Azithromycin works wonders in COVID-19 patients. Unfortunately this has led to some people stating that this combination of drugs, or just hydroxychloroquine is a miracle cure and has led to shortages of hydroxychloroquine and even one death from someone who thought that they were protecting themselves from COVID-19 by consuming chloroquine phosphate (pool cleaner) but ended up killing themselves https://www.cnn.com/2020/03/23/health/arizona-coronavirus-chloroquine-death/index.html, there is up to date information on chloroquine and hydroxychloroquine at the CDC: https://www.cdc.gov/malaria/new_info/2020/chloroquine.html. Hydroxychloroquine is an FDA approved drug for certain immune deficiencies, including lupus and now these patients are having trouble getting drugs that they need and work.

It is really hard physically and ethically to do clinical trials to prove that a drug works during a pandemic, but people are trying very hard. So far the data on chloroquine and hydroxychloroquine as treatments for COVID-19 are inconclusive. The “gold standard” for a clinical trial is a double-blind placebo-controlled trial where neither the patient nor the provider know if the patient is getting the drug or a placebo (a sugar pill, or something similar that has no medicine in it, but is otherwise similar to the medicine). It is also important that a clinical trial has sufficient numbers of people who are as comparable to each other as possible in order for the trial to be statistically significant and sufficiently convincing to be used by medical professionals (which I am not!).

The trial which got all of the press about a week ago has a number of issues. One is that it was an “open label” trial, where all of the patients got to choose if they got drug or not, so they were self-selected and not really comparable to each other. There were also only 6 patients reported in the Hydroxychloroquine and Azithromycin part of the trial at the end. Apparently at least 1 person in this treatment group died and 5 others left the trial for unclear reasons. The manuscript itself was submitted for peer review (where other, presumably independent, scientists critique the manuscript) one day before it was accepted. Generally peer review takes weeks or more, not a single day. The chief editor of the journal is also an author on the paper, which could be a conflict of interest, as it is the chief editor who decides what gets published or not in the journal. Another group has done a far better job than I commenting on the paper link below.

Take home message: Hydroxychloroquine plus Azithromycin is NOT a wonder drug/treatment yet, and far more trials (many of which are ongoing with both Chloroquine and Hydroxychloroquine, 20 at last count) are required before it can be show to be effective and used in medical practice, I hope to see them soon. So leave the Hydroxychloroquine for the people who need it, those with lupus and other autoimmune diseases.

(See https://www.youtube.com/watch?v=8A3jiM2FNR8) and https://www.cebm.net/covid-19/chloroquine-and-hydroxychloroquine-current-evidence-for-their-effectiveness-in-treating-covid-19/

https://zenodo.org/record/3725560#.Xn_tVdNKiYU

Question on Coronaviruses in local bats:

To my understanding, there are Coronaviruses in US bats (not sure about OR and WA), but not closely related to SARS-CoV (1 or 2).  Here is an article about it: 

• http://wwwnc.cdc.gov/eid/article/13/9/07-0491_article.htm 

There may be some other papers on the subject, I do not know.  I discuss this in my Coronavirus lecture on my YouTube channel, (YouTube.com/c/KenStedman) if you are interested in more details. 

-Ken Stedman

On Sun, Mar 15, 2020 at 12:02 PM wrote:

Dr. Stedman,Considering your statement that COVID-19 originated in bats from China, is it possible that Oregon and Washington bats carry similar viruses?

SARS-CoV-2 on surfaces MedRxiv preprint.

A preprint (a scientific article that has not yet undergone peer-review, so is not considered “vetted” yet) was recently posted on MedRxiv and has generated quite a lot of press. https://www.medrxiv.org/content/10.1101/2020.03.09.20033217v1.full.pdf I wanted to put this work in some context.

To start with, this is very important work and it cannot be done by most scientists. It has to be done in a high security laboratory, also known as BioSafety Level-4 (BSL-4) because we currently have no treatment for SARS-CoV-2 (they call it HCoV-19 in the preprint, which is a little confusing) and it can be deadly. The work was done at the National Institutes of Health BSL-4 lab in Hamilton, Montana at the Rocky Mountain Labs.

The researchers put the virus in a nebulizer with some liquid to put the virus into small liquid droplets, kind of an artificial cough or sneeze. The droplets they made are smaller than 5 micrometers, so called aerosols. They also put the virus directly on various surfaces, copper, stainless steel, plastic, and cardboard. After they did these things to the virus, they waited and tested to see if the virus could make cells sick. To do this, they put the virus on cells in a petri plate (not exactly a petri plate, but similar). Then they used smaller and smaller amounts of the virus (dilutions) until it no longer made the cells sick. This is called a TCID50 test, (Tissue Culture, Infectious Dose 50% test). It is a pretty easy test to do, even I have done some (not with SARS-CoV-2, with flu vaccine!). You can tell how active or “viable” (the term used in the preprint) the virus is by how much you can dilute the virus before it stops making the cells sick. All of these experiments were done in controlled laboratory conditions (65% relative humidly (RH) and 21-23C for aerosols, 40% RH for surfaces).

The researchers found that the virus lost about 90% of its viability in aerosols after 3 hours. The virus lost about 99.9% of its viability, on plastic by 72 hours and on stainless steel by 48 hours but was still detectable. On copper the virus lost over 99% of its viability after 4 hours, and could not be detected after 4 hours. No virus could be detected after 24 hours on cardboard. Loss of viability in all conditions was exponential, so much more viability was lost earlier. The half-life (time until 1/2 of viability was gone) for aerosols was about 2.5 hours, for copper 3.5 hours, for cardboard 8.5 hours, for stainless steel 13 hours and for plastic 16 hours.

These viability values are all very similar to SARS-CoV-1, which is more deadly than SARS-CoV-2 but spreads much less well. So it is not clear why SARS-CoV-2 seems to spread much better than SARS-CoV-1, it does not appear to be due to it’s stability on aerosols or surfaces. The researchers state that SARS-CoV-2 transmission via aerosols (very small droplets) and surfaces is possible. They do not state, but I understand, that this means that the main means of transmission is probably directly through respiratory droplets, so keep your distance and cover your cough! Since transmission via surfaces is possible, also WASH YOUR HANDS!

There are a couple of caveats about this paper, all acknowledged by the researchers. All experiments were done in a controlled lab environment, what happens in the “real world” is less clear. More importantly, you may have noticed that I used viability instead of infectivity (as did the authors). We do not know what the infectious dose for SARS-CoV-2 is [N.B. I have been reminded, thanks Charles Haas, that infectious dose is a bit of a misnomer, it is really more of a statistical issue, but I did not want to get into details]. So maybe when the virus is in an aerosol or on a surface it could lose too much viability to be infectious, even if it is still detectable with this TCID50 test. These are very important numbers to know, but will be hard to test, since we can’t infect people with the virus in an experiment.

Comments on: “What I am doing for the upcoming COVID-19 (coronavirus) pandemic” e-mail.

Here is another “viral” e-mail.

Subject: What I am doing for the upcoming COVID-19 (coronavirus) pandemic

Dear Colleagues, as some of you may recall, when I was a professor of pathology at the University of California San Diego, I was one of the first molecular virologists in the world to work on coronaviruses (the 1970s). I was the first to demonstrate the number of genes the virus contained. Since then, I have kept up with the coronavirus field and its multiple clinical transfers into the human population (e.g., SARS, MERS), from different animal sources. The current projections for its expansion in the US are only probable, due to continued insufficient worldwide data, but it is most likely to be widespread in the US by mid to late March and April.

Here is what I have done and the precautions that I take and will take. These are the same precautions I currently use during our influenza seasons, except for the mask and gloves.:

1) NO HANDSHAKING! Use a fist bump, slight bow, elbow bump, etc.

2) Use ONLY your knuckle to touch light switches. elevator buttons, etc.. Lift the gasoline dispenser with a paper towel or use a disposable glove.

3) Open doors with your closed fist or hip - do not grasp the handle with your hand, unless there is no other way to open the door. Especially important on bathroom and post office/commercial doors.

4) Use disinfectant wipes at the stores when they are available, including wiping the handle and child seat in grocery carts.

5) Wash your hands with soap for 10-20 seconds and/or use a greater than 60% alcohol-based hand sanitizer whenever you return home from ANY activity that involves locations where other people have been.

6) Keep a bottle of sanitizer available at each of your home's entrances. AND in your car for use after getting gas or touching other contaminated objects when you can't immediately wash your hands.

7) If possible, cough or sneeze into a disposable tissue and discard. Use your elbow only if you have to. The clothing on your elbow will contain infectious virus that can be passed on for up to a week or more!

What I have stocked in preparation for the pandemic spread to the US:

1) Latex or nitrile latex disposable gloves for use when going shopping, using the gasoline pump, and all other outside activity when you come in contact with contaminated areas.

Note: This virus is spread in large droplets by coughing and sneezing. This means that the air will not infect you! BUT all the surfaces where these droplets land are infectious for about a week on average - everything that is associated with infected people will be contaminated and potentially infectious. The virus is on surfaces and you will not be infected unless your unprotected face is directly coughed or sneezed upon.  This virus only has cell receptors for lung cells (it only infects your lungs) The only way for the virus to infect you is through your nose or mouth via your hands or an infected cough or sneeze onto or into your nose or mouth.

2) Stock up now with disposable surgical masks and use them to prevent you from touching your nose and/or mouth (We touch our nose/mouth 90X/day without knowing it!). This is the only way this virus can infect you - it is lung-specific. The mask will not prevent the virus in a direct sneeze from getting into your nose or mouth - it is only to keep you from touching your nose or mouth.

3) Stock up now with hand sanitizers and latex/nitrile gloves (get the appropriate sizes for your family). The hand sanitizers must be alcohol-based and greater than 60% alcohol to be effective.

4) Stock up now with zinc lozenges. These lozenges have been proven to be effective in blocking coronavirus (and most other viruses) from multiplying in your throat and nasopharynx. Use as directed several times each day when you begin to feel ANY "cold-like" symptoms beginning. It is best to lie down and let the lozenge dissolve in the back of your throat and nasopharynx. Cold-Eeze lozenges is one brand available, but there are other brands available.

I, as many others do, hope that this pandemic will be reasonably contained, BUT I personally do not think it will be. Humans have never seen this snake-associated virus before and have no internal defense against it. Tremendous worldwide efforts are being made to understand the molecular and clinical virology of this virus. Unbelievable molecular knowledge about the genomics, structure, and virulence of this virus has already been achieved. BUT, there will be NO drugs or vaccines available this year to protect us or limit the infection within us. Only symptomatic support is available. I hope these personal thoughts will be helpful during this potentially catastrophic pandemic. You are welcome to share this email.

Good luck to all of us!

James Robb, MD FCAP

While I have a great deal of respect for Dr. Robb, a respected pathologist, he states at the beginning of the e-mail “Since then [the late 1970s, 40 years ago], I have kept up with the coronavirus field and its multiple clinical transfers into the human population (e.g., SARS, MERS), from different animal sources.” and then at the end “Humans have never seen this snake-associated virus before and have no internal defense against it.” He does not appear to have published on Coronaviruses since 1981 (then again, I have never published on Coronaviruses, so you can decide).

The evidence for SARS-CoV-2 having anything to do with snakes has long been debunked and leads me to question the “I have kept up with the coronavirus field” statement.

That being said, I agree with most of his precautions, I find the use of gloves and wipes to be excessive. Gloves can be contaminated as easily as hands, so they must be discarded, which in my opinion is rather wasteful. Hands are easier to wash. However, I disagree with the stocking and other comments. The ACE2 receptor that SARS-CoV-2 binds to is also present on gut epithelial cells, which is probably why viral RNA can be found in fecal matter and closely related viruses may replicate in bats (not snakes!) in the gut. See my previous blog post about surfaces. Surgical masks are usually misused and are only really preventative when someone is ill.

It is also unlikely that someone else will be rubbing the elbow of your shirt/blouse in their face, the main reason to cough into your elbow is so that you don’t spread your droplets to other people.

I would love to see data on Zinc in a properly controlled blinded trial (lozenges without zinc and lozenges with zinc). To my knowledge none exist. I am pretty certain that zinc lozenges have no effect on disease progression due to SARS-CoV-2 infection. I also am extremely skeptical when a brand is mentioned.

Critical reading of COVID-2 "Advice" letter

The letter below or some variation thereof has been circulating on the Internet. There are a number of issues with the letter that I will outline below the letter.

I received this from a friend of mine who’s brother is on the Stanford hospital board. This is their feedback for now on Corona virus: The new Coronavirus may not show signs of infection for many days. How can one know if he/she is infected? By the time they have fever and/or cough and go to the hospital, the lung is usually 50% Fibrosis and it's too late. Taiwan experts provide a simple self-check that we can do every morning. 1) Take a deep breath and hold your breath for more than 10 seconds. If you complete it successfully without coughing, without discomfort, stiffness or tightness, etc., it proves there is no Fibrosis in the lungs, basically indicates no infection. In critical time, please self-check every morning in an environment with clean air. Serious excellent advice by Japanese doctors treating COVID-19 cases: 1) Everyone should ensure your mouth & throat are moist, never dry. Take a few sips of water every 15 minutes at least. Why? Even if the virus gets into your mouth, drinking water or other liquids will wash them down through your throat and into the stomach. Once there, your stomach acid will kill all the virus. If you don't drink enough water more regularly, the virus can enter your windpipe and into the lungs. That's very dangerous. Please send and share this with family and friends. Take care everyone and may the world recover from this Coronavirus soon. Part 2 on CORONAVIRUS- Last evening dining out with friends, one of their uncles, who's graduated with a master's degree and who worked in Shenzhen Hospital (Guangdong Province, China) sent him the following notes on Coronavirus for guidance: 1. If you have a runny nose and sputum, you have a common cold 2. Coronavirus pneumonia is a dry cough with no runny nose. 3. This new virus is not heat-resistant and will be killed by a temperature of just 26/27 degrees. It hates the Sun. 4. If someone sneezes with it, it takes about 10 feet before it drops to the ground and is no longer airborne. 5. If it drops on a metal surface it will live for at least 12 hours - so if you come into contact with any metal surface - wash your hands as soon as you can with a bacterial soap. 6. On fabric it can survive for 6-12 hours. normal laundry detergent will kill it. 7. Drinking warm water is effective for all viruses. Try not to drink liquids with ice. 8. Wash your hands frequently as the virus can only live on your hands for 5-10 minutes, but - a lot can happen during that time - you can rub your eyes, pick your nose unwittingly and so on. 9. You should also gargle as a prevention. A simple solution of salt in warm water will suffice. 10. Can't emphasis enough - drink plenty of water! THE SYMPTOMS 1. It will first infect the throat, so you'll have a sore throat lasting 3/4 days 2. The virus then blends into a nasal fluid that enters the trachea and then the lungs, causing pneumonia. This takes about 5/6 days further. 3. With the pneumonia comes high fever and difficulty in breathing. 4. The nasal congestion is not like the normal kind. You feel like you're drowning. It's imperative you then seek immediate attention. SPREAD THE WORD - PLEASE SHARE."

I am always skeptical when people use anecdotal evidence;  "friend of mine whose brother", "Taiwan experts", "Japanese doctors", friend's uncles. I also don't like when an e-mail states "please share".  I trust the WHO's symptom's page (below) which says that sore throat is a "sometimes" symptom.  Dry cough and fever are the most common symptoms.  Here are a couple more points: 

• I have a big issue with the 26-27C statement, the virus replicates in the lungs which are at 37C.   

• Lung fibrosis is lung damage, the problem with COVID-19 is pneumonia (liquid in the lungs) not fibrosis.  

• There is also an issue with stomach acid inactivating the virus, as some Coronaviruses, particularly bat Coronaviruses, where SARS-CoV-2 probably came from, are known to replicate in the gut (we don't know about SARS-CoV-2, which is the current problem). In fact people have found SARS-CoV-2 sequences in human stool samples, not sure if they have found infectious virus yet, but it does NOT appear that fecal transmission is a major route of transmission for SARS-CoV-2, it is a respiratory virus.  

• The data for virus survival on surfaces is a little less clear.  There have been some recent experiments with SARS-CoV-2 on surfaces that show that it can still infect cells in a petri dish after being on different surfaces for varying lengths of time, up to 10s of hours.  Whether the virus is infectious to humans after that time is less clear.  It does lose infectivity in the petri dish test over time. 

• No idea about cold vrs. hot water, in general hydration is good, I would love to see some data on this other than anecdotes (reminder the plural of anecdote is NOT data).

• I would say wash your hands after touching surfaces that might be contaminated before touching your face, every 5-10 minutes seems excessive (>150 times a day), unless you are touching lots of common surfaces and are very close to a sink all day. 

• Same issue with gargling, I have not seen any data on this.