Sunday, March 29, 2020

Surviving the Coronavirus: Part 8

Evil China Government Edition

Those of you previously familiar with the august blog realize that American governments (at federal, state, and local levels) are far from being exceptions to my skeptical scorn. The Skeptical Juror blog has, until this coronavirus crisis, focused on the great harm our governments (at the federal, state, and local levels) have inflicted on some of our fellow citizens. Some of those who allegedly serve us, far too many of them, have carelessly, foolishly, and all too often intentionally used our legal system to bring down great harm, even death, on the innocent among us.

It should therefore come as no surprise to my ever dwindling list of followers that I will make no skeptical exception for those who govern the Chinese people. I do not trust the Chinese government any further than I can throw it. In this specific case, my metaphor server is not failing me. I cannot throw the Chinese government even an angstrom; I trust the Chinese government not even a whit, whatever the hell a whit is.

I'll waste just a bit of textual white space to make a lame effort to calm all the hair-trigger racist-labelers out there. I have no unique animus or dislike of the Chinese people. They are my fellow Earthlings. I feel a kindred spirit with them knowing that, in both absolute and percentage numbers, they suffer far greater harm (than we do) at the hands of those who allegedly serve us.

With that background, in that context, I herein discuss a report from China claiming that hydroxychloroquine is not effective as a treatment for the Wuhan coronavirus. The report is mostly in Chinese, and my skills in that regard are somewhat limited. The abstract, however, is in English. I'll therefore provide a condensed version of the abstract so that you can consider it yourself, kinda like a pop quiz, before I tell you why I am skeptical of it.

Sharpen your pencils, gather your wits about you, and prepare to focus. Here we go.
Objective: To evaluate the efficacy and safety of hydroxychloroquine (HCQ) in the treatment of patients with common coronavirus disease-19 (COVID-19). 
Methods: We prospectively enrolled 30 treatment-na├»ve patients with confirmed COVID-19 after informed consent at Shanghai Public Health Clinical Center. The patients were randomized 1:1 to HCQ group and the control group. Patients in HCQ group were given HCQ 400 mg per day for 5 days plus conventional treatments, while those in the control group were given conventional treatment only. [...] 
Results: One patient in HCQ group developed to severe during the treatment. On day 7, COVID-19 nucleic acid of throat swabs was negative in 13 cases in the HCQ group and 14 cases in the control group. The median duration from hospitalization to virus nucleic acid negative conservation was 4 days in HCQ group, which is comparable to that in the control group, 2 days. The median time for body temperature normalization in HCQ group was 1 day after hospitalization, which was also comparable to that in the control group. Radiological progression was shown on CT images in 5 cases of the HCQ group and 7 cases of the control group, and all patients showed improvement in follow-up examination. Four cases of the HCQ group and 3 cases of the control group had transient diarrhea and abnormal liver function. 
Conclusions: The prognosis of common COVID-19 patients is good. Larger sample size study are needed to investigate the effects of HCQ in the treatment of COVID-19. Subsequent research should determine better endpoint and fully consider the feasibility of experiments such as sample size.
Bonus points to those of you who were skeptical of the integrity of my condensed version of the report's abstract. Gold stars to those of you what actually compared my condensed version with the actual abstract. You were probably shocked when you realized that I removed some percentages, ranges, and statistical confidence levels without noting the omissions with bracketed ellipses. I did so [I lamely claim, after the fact] solely in a good faith effort to make my condensed version of the paper's abstract more readable and understandable to the reader and understander. Also, the delay provided you with time to consider your skepticism, presuming you have any.

Here are the issues that jumped out at me.

#1. Why only 30 patients? Wuhan alone has tens of thousands of cases that could be studied, and China has apparently been routinely using chloroquine in some form as part of their treatment. So why only 30 patients? Why not a huge observational study of documented cases across China?

#2. What were the demographics of the test and the control groups? I realize you said that you randomized them between the two groups, but you didn't give us the demographics of the starting pool of 30 patients. Did you take them all from a senior citizens center? That seems doubtful, since the fatality rate probably would have been higher. Did you take them all from a youth athletic club? Given that all but one of the patients responded well to whatever treatment was provided, I'm going to guess that the test population consisted largely of younger people.

#3. And just how many times did you randomize before you settled on your test and control groups?  Only once? More than once? Be honest with us. This issue relates back to issue #2. What was the demographics of your final test and control groups? How did they compare to one another? Was either group representative of the entire population?

#4. What the hell was the "conventional care" provided to the control group? You never mentioned that. Based on your own test results, I think we want whatever you were giving to them.

I became aware of this report a few days ago. Since I had written several times of some version of chloroquine as being a good candidate for a possible treatment, "my top pick" as I recall, I pondered about writing a post presenting contradictory evidence.

"Write the post," said the little devil on my right shoulder, accusing me of confirmation bias should I not."

"Ignore that bastard," said the little devil on my left shoulder, accusing me of carelessly spreading false information should I write of the report.

"You're tired of writing these posts," said the little devil in my left ear. "Do some of the other stuff you have to do. Do something you want to do. Take some time for yourself. You deserve it."

"You have an obligation," said the little devil in my right ear. "You didn't have to start this series, which you repeatedly refer to as an august series, even though most your readers have no idea what you mean by that. You can't just stop now, as things are getting worse, just before they will get real bad, just when you might make a difference, even if only an itsy bitsy, teeny weenie difference."

So I listened to the devil in my left ear, and I went and worked on my impending series of books about Louise Conan Doyle being the actual author of the Sherlock Holmes adventure. Yesterday was the most pleasant, least stressful day I've had in a while. I took some time for myself. I deserved it.

I have this nagging guilt problem though. I still have database design work I should be doing to generate an income, which I still need. I still have several tons of work to do on a specific wrongful conviction case that I've been trying to correct for over a decade. I still have responsibilities to help prepare and protect those close to me from the coronavirus onslaught that is rapidly approaching. And I still have this blog post to write, since the readership has increased slightly and must be waiting with baited breath with bated breath anxiously.

Also, and this is the factor that finally compelled me to write this post, I've come across an 80-page Norwegian paper that describes how broadly, persistently, and effectively China is using chloroquine as a treatment. In my quick summary of that lengthy paper, China not walking the talk. They are telling others that hydroxychloroquine is not worth using, but they are using it themselves, big time.

The paper is entitled "Essential Takeaways from China’s Response to COVID-19." It is authored by Yun Zhou (biomedical Researcher from Wuhan, living in Norway), Dr. Niels Chr. Danbolt (MD, professor, University of Oslo), and Stefan Krauss (MD, professor, University of Oslo). I present their key points, strategy, and additional point below. I excise some of their footnotes and parentheticals. Other than that, everything that follows, beneath the divider, is theirs, not mine. See the original if you prefer. Otherwise, continue reading this most august blog post to the end.

I congratulate the authors on their paper, their professionalism, and their effort to save lives.


Key points:

1. The morbidity and mortality rates are so high that the virus causes the healthcare systems to be overwhelmed. The virus must be contained, and that explains the massive Chinese response with extensive quarantine measures.

2. While an approved drug for COVID-19 treatment does not exist, some drugs appear to be effective in treating the disease. One of these is the malaria drug chloroquine (both the phosphate version, and the hydroxy-variant). Chloroquine appears to be most effective if given early in the disease when symptoms are mild. This was reported in Chinese newspapers and other state-controlled media as early as early February 3, 4. Chloroquine is the drug most often mentioned in Chinese newspapers. It simple and fast to produce in large quantities and its side effects are well known and controllable.

3. For patients not tolerating or responding to chloroquine, three other drugs have been tried: Remdesivir, Lopinavir/Ritonavir and Umifenovir (Arbidol). All of these have moderate to severe side-effects, they are less studied, and they are more expensive to produce.

4. Chinese authorities have, according to our open-source intelligence, placed large orders on chloroquine, and we have got the impression that they maybe using this drug on a vast scale. Guangzhou Baiyunshan Guanghua Pharma has resumed full production capacity and has a daily capacity of 2 million tablets, suggesting that the Chinese authorities believe that chloroquine is effective.

5. A key point is that Western publications have not caught up with the above information as it is only available in Chinese. The authors of this memo are concerned that Western authorities (e.g. CDC and WHO) are unaware of important information that can be used to effectively deal with the COVID-19 pandemic. Information on the potential benefits of chloroquine for treatment of COVID-19 mediated disease is beginning to appear in Western media.

6. To what extent chloroquine treatment has been a key factor in the apparent Chinese success in fighting COVID-19 is unknown, but the evidence for a key role of chloroquine in this epidemic is compelling and needs to be investigated.

7. Our sources indicate that chloroquine administered at a sufficiently early stage may lower the number of patients that will require hospitalization.  In fact, this is what the Chinese have tried to do. Early treatment of infected people in Wuhan City reduced the percentage of severe conditions from 38% to 18%. In contrast, when the disease has progressed into a serious condition requiring intensive care admission and artificial ventilation, the treatment is less effective and a significant number of patients will die.

To summarize:

a. There is an existing drug, well tested, well documented and with manageable side effects, which is neither exceptionally expensive nor difficult to produce and is fairly effective if administered at the correct time.

b. In order to maximize the effectiveness of chloroquine it will be necessary to identify infected patients as early as possible through extensive testing with a rapid turn-around time.

8. There are also rumors that chloroquine may prevent the development of the disease if given at smaller doses to asymptomatic individuals.  If this is correct, then prophylactic treatment of people at risk (e.g. health personnel and individuals with underlying conditions) may be possible.

9. A high percentage of infected people may be absent from work for months and the Chinese are becoming stricter with respect to declaring an infected patient disease-free. Effective March 6th, 2020, they only release infected patients from quarantine after they have developed COVID-19 neutralizing antibodies. Infected patients with no or minimal antibody response are kept in quarantine as there is increasing evidence that they continue to shed virus and therefore can infect others. We have also been told by friends in Wuhan that China is considering 4 weeks of quarantine rather than the current recommendation of 2 weeks.

10. There are speculations that some patients die from an uncontrolled immune response (a.k.a. “cytokine storm”) and the immune suppressing drug Tocilizumab is being tested to prevent or stop this serious complication.

11. There are discussions whether ADE (antibody-dependent enhancement) may complicate vaccine development and pose a significant risk if reinfection occurs with a mutated virus.

12. Because the disease originated in animals, it may be worthwhile to check whether domestic animals need protection.

Potential strategy implications based on the above findings:

1. More resources need to be allocated to learn more about what has actually happened in China and what the Chinese have learnt from it. Relevant agencies should search Chinese sources and also interview Chinese doctors and other relevant persons. This latter part may be somewhat challenging, for obvious reasons.

2. The capacity for early diagnosis need to be radically expanded and combined with a decentralized access to relevant drugs (including chloroquine phosphate and/or hydroxychloroquine). The majority of the infected may then be able to treat themselves at home under remote medical guidance. This could have major implications because the number of patients admitted to hospitals would decrease and fewer people would need long sick-leaves. This in turn would also reduce the infection rate among healthcare workers.

3. The production of chloroquine in sufficient amounts to cover the entire US population, and hopefully also those of US allies, should be contemplated. At present, we are dependent on the Chinese for production both of chloroquine and the central materials needed to make it.

4. The West should increase own production of a panel of anti-viral drugs and antibiotics. Anti-viral drugs reported by the Chinese and others to be effective, are not available in sufficient quantities.

An additional point:

It is currently speculated whether chloroquine is able, not only to cure, but also prevent the onset of a Corvid-19 infection. How can we get an indication if it can work prophylactically? Patients suffering from rheumatoid arthritis and patients with systemic lupus erythematosus are often receiving hydroxy-chloroquine to keep the disease in check. If these patients do not get infected (or have a reduced risk to get infected) with coronavirus, then a likely interpretation is that chloroquine may have a protective effect. We got the following information from a hospital in Wuhan: "In the early stage of the study group, through the clinical analysis of 178 patients with new coronavirus received by the hospital from December 2019, it was found that none of them has systemic lupus erythematosus. After that, in the consultation of 80 patients with systemic lupus erythematosus treated by dermatology department of the hospital, it was found that they were not infected with new coronavirus pneumonia."

This is at current only an indication. We therefore propose that the US authorities explores health registries to identify a potential connection between hydroxychloroquine treatment and Covid-19 prevalence. Information could be gained within days. Particular good sources may be European countries and South Korea, but also China. If hydroxychloroquine has a protective function, we may -in combination with traditional measures (quarantine etc.) – be able to bring the transmission rate below 1 (each infected will infect on average less than 1 other person) and the epidemic may be contained in short time.

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