Copyright 2021 Robert Clark
There has been a present push to reopen the economies and the schools. Unfortunately, there has been a present surge in COVID-19 cases. Some countries particularly the Asian countries have COVID-19 death rates at 1/100th those in Western countries:
The pandemic appears to have spared Africa so far. Scientists are struggling to explain why.
Commenters on this difference have mentioned the first few of these as the cause. But quite puzzling is the aversion of those who have commented on the question to consider the possibility that difference in treatments might at least be a part of cause.
It is a well-known fact that antiviral therapies are best applied soon after infection, for example, for influenza and HIV. And this had been the recommendation of the CDC against the flu and the pandemic H1N1:
Filed Under: Influenza, General; H1N1 2009 Pandemic Influenza; Public Health
By: Robert Roos | Sep 08, 2009
Sep 8, 2009 (CIDRAP News) Revised recommendations from federal health officials on the use of influenza antiviral drugs suggest that clinicians consider providing prescriptions over the phone for high-risk patients as a way to start treatment faster if they come down with flu symptoms.
At the same time, the recommendations released today from the Centers for Disease Control and Prevention (CDC) suggest that clinicians try "watchful waiting" when high-risk patients have been exposed to flu but remain healthy, rather than prescribing a preventive antiviral right away. The recommendations cover both pandemic H1N1 and seasonal flu.
Shoya Iwanami, et. al.
Therapy for Early COVID-19
A Critical Need
Peter S. Kim, MD1; Sarah W. Read, MD, MHS1; Anthony S. Fauci, MD2
JAMA. 2020;324(21):2149-2150. doi:10.1001/jama.2020.22813
May 11, 2018,12:25am EDT
Will Real World Performance Replace RCTs As Healthcare's Most Important Standard?
David Shaywitz Contributor
The Beneficial Impacts of Real-World Evidence in Drug Development
Posted on August 1st, 2019 by Xuanyan Xu in Pharma R&D
Real-world evidence, which is based on data that is gathered during routine clinical practice, has the potential to make a meaningful impact in nearly every phase of the life of a drug. That means RWE is relevant to:
Early discovery – “RWE has the potential to be used early in drug discovery and development programs, facilitating product development by identifying diseases or indications that represent a significant burden in populations,” explains this paper on real-world evidence, also noting the example of the NIH using electronic health records to support differentiation of patients’ needs.
Published online 2018 Aug 29. doi: 10.12688/f1000research.13585.2
Real world evidence (RWE) - a disruptive innovation or the quiet evolution of medical evidence generation?
Sajan Khosla 1, Robert White 2, Jesús Medina 3, Mario Ouwens 4, Cathy Emmas 5, Tim Koder 6, Gary Male 6, Sandra Leonard 2
PMID: 30026923 PMCID: PMC6039945 DOI: 10.12688/f1000research.13585.2
Doctors whose expertise is in rheumatic diseases for example could prescribe HCQ. They would be intimately familiar with its side effects and would know what to look for. And doctors for example who routinely prescribe interferon would know its side effects and contraindications. This way you could have a maximal safety approach while allowing a wide variety of different medications to be tested at the same time.
There are about a million doctors in the U.S. Imagine all that knowledge, all that experience, all that creativity, all being brought to bear in toto in finding effective treatments for this, and other diseases as well. Furthermore, imagine this all happening in real time, critically important in the midst of a pandemic.
A new possible treatment for COVID-19: interferon alpha.
Nathan Peiffer-Smadja, Yazdan Yazdanpanah
Published:November 12, 2020
Another is favipiravir for early treatment:
Posted: 26 Oct 2020
Tatiana Ruzhentsova, Pavel Chukhliaev, et.al.
November 16, 2020
Efficacy and Safety of Favipiravir, an Oral RNA-Dependent RNA Polymerase Inhibitor, in Mild-to-Moderate COVID-19: A Randomized, Comparative, Open-Label, Multicenter, Phase 3 Clinical Trial
Zarir F.Udwadiaa, et.al.
It is notable, and unfortunate, that these successful trials showing effective antiviral use when used early occurred in trials overseas.
Triple combination of interferon beta-1b, lopinavir–ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial
Prof Ivan Fan-Ngai Hung, MD et al.
Published:May 08, 2020
Anti-inflammatories for serious disease.
Some anti-inflammatories have shown to be effective for patients that need oxygen such as those on ventilators, including dexamethasone and tocilizumab. But the reduction in lung inflammation can be measured in real time by detecting markers such as IL-6 and CRP and even in CT scans. Then the effectiveness of these anti-inflammatories can also be observed on short time scales. See the discussion in the update dated from 6/26/2020 here:
There, is discussed this report:
Published: 15 May 2020
Low dose of hydroxychloroquine reduces fatality of critically ill patients with COVID-19.
Bo Yu, Chenze Li, Peng Chen, Ning Zhou, Luyun Wang, Jia Li, Hualiang Jiang & Dao-Wen Wang
Science China Life Sciences (2020)
These data demonstrate that addition of HCQ on top of the basic treatments is highly effective in reducing the fatality of critically ill patients of COVID-19 through attenuation of inflammatory cytokine storm. Therefore, HCQ should be prescribed as a part of treatment for critically ill COVID-19 patients, with possible outcome of saving lives.
hydroxychloroquine, IL-6, mortalities, COVID-19
Quite notably the authors observed in real time a reduction in the level of IL-6, a key marker for inflammation, during the treatment with HCQ. So from both CT imaging and inflammation marker readings we could tell if HCQ or other anti-inflammatories were having a beneficial effect on patients under severe disease.
It is important to understand the reason why it was that several studies from Asian countries showed positive effects for HCQ while several studies in the Western countries did not.
After we examined several of the negative reports on HCQ published on Western studies, we observed multiple times that the effectiveness of HCQ was obscured in the presentation of their data. We will offer no hypotheses as to the reasons why its effectiveness was obscured in the reports on the Western studies.
For example, two of the most widely-cited negative HCQ reports by Geleris et al. and Rosenberg et al. omitted from the conclusions that the data showed HCQ cut mortality in half for ventilated patients. Adverse events for a medication must be reported, and this has been done extensively for HCQ. But by the same token, subcases with benefit for the medication should also be reported.
The report by Geleris et. al. here:
Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19.
June 18, 2020
Editor’s Note: This article was published on May 7, 2020, at NEJM.org.
N Engl J Med 2020; 382:2411-2418
Left out of the paper itself, and included only in the Supplementary Appendix, was this Table:
You see the mortality in the HCQ group for intubated patients, i.e., those on invasive mechanical ventilation, was 49/154 = .318, or 31.8%. But the mortality for intubated patients for the non-HCQ group was 17/26 = .654, or 65.4%. So the mortality was halved in the HCQ group for intubated patients.
Actually, it may even be better than this. As an observational trial, the treated patients are likely not evenly distributed among patients with different comorbidities or with level of disease compared to the controls. Quite often the treatments are given to the sicker patients. Then usually in such observational studies as in this one statistical adjustments have to be made to compensate for the fact the sicker patients were given the medication which would skew the results against the treated group.
But in the Table S1 this appears to be just the raw data. Then after the statistical adjustments for HCQ being given to the sicker patients the mortality benefit for HCQ over the controls for ventilated patients might be even higher.
The Rosenberg et. al. paper is here:
Association of Treatment With Hydroxychloroquine or Azithromycin With In-Hospital Mortality in Patients With COVID-19 in New York State
Eli S. Rosenberg, PhD1; Elizabeth M. Dufort, MD2; Tomoko Udo, PhD1; et al
JAMA. 2020;323(24):2493-2502. doi:10.1001/jama.2020.8630
The table showing the mortality specifically for ventilated patients from the supplementary file here:
You see HCQ used alone reduced mortality specifically for ventilated patients by a factor of 0.60 and HCQ used with AZT by a factor of 0.53. But once again this appeared not in the paper itself but only in a supplementary file.
It's dismaying that this data wasn't discussed among the conclusions the authors made in their articles. First of all appearing only in the supplementary files, not in the articles proper, very few people would have taken the time to find and read these tables, certainly not the science journalists reporting on the research and not even most doctors disseminating this information to the public at large and to the policy makers making decisions on use of HCQ.
But what's really dismaying is both of these took place in New York. In New York at the time the mortality for patients on ventilators was in the range of 80%:
USA TODAY Updated April 10, 2020
Doctors were desperate to find a treatment to help save ventilated patients lives, but the effectiveness of HCQ for those on ventilators was not made apparent to them.
The usefulness of HCQ for those on mechanical ventilation would have been even more apparent because of that report appearing in a Chinese journal that we cited above by Bo Yu et al., "Low dose of hydroxychloroquine reduces fatality of critically ill patients with COVID-19".
That report showed mortality cut by 60% for ventilated patients taking HCQ. But with the two widely cited American papers making a blanket statement of "no benefit", this Chinese report barely registered.
It's possible the authors and/or reviewers and/or editors calculated the significance levels and decided they didn't rise to the standard significance level of 0.05. If they did calculate the significance levels then they should have been reported in the papers. But in any case, all medical researchers are aware of the fact that a result not rising to statistical significance level does not mean the result is wrong. It could also simply mean the sample size wasn't large enough for it to rise to statistical significance.
All too often this qualifier is left out of reports on medical studies, and it is certainly left out on news reports on the studies. Then the public and other doctors are simply left with the incorrect conclusion that the treatment has been proven not to work.
With a difference this large of the deaths being cut in half for those on ventilators, the significance levels should have been reported in the papers. And it should have been acknowledged in the papers if the significance level wasn't at the standard level of 0.05 for the sample size used, that larger studies would be needed to determine if the result was real or just a statistical artifact.
As we mentioned, studies have shown multiple different anti-inflammatories such as steroids can be beneficial for COVID-19. Indeed this happened with dexamethasone in the RECOVERY trial, among others. It is simply unreasonable then to suppose HCQ as a very effective anti-inflammatory is not. It’s probably the reason so many HCQ studies, including ones claiming “no benefit”, did show benefit.
An astonishing instance of this occurred in the RECOVERY trial. The RECOVERY trial was a randomized-controlled trial (RCT), which are called the "gold-standard" of medical studies. Because it was negative towards HCQ, it was frequently cited as evidence of HCQ having no effect.
RCT's aren't perfect of course. There can be flaws in interpreting the data, there may not be sufficient numbers of subjects to draw a strong conclusion. They can use the wrong dosage, etc. And unfortunately there can also be cases where researchers falsify data.
We do not consider this last possibility likely to be the case with the RECOVERY trial. However, what we found did happen in the RECOVERY trial was nearly as bad in regards to accurately assessing the effectiveness of HCQ: while the data presented was correct, the way it was presented obscured the HCQ effectiveness.
Here's the HCQ report from the RECOVERY trial:
Effect of Hydroxychloroquine in Hospitalized Patients with Covid-19
The RECOVERY Collaborative Group
November 19, 2020
N Engl J Med 2020; 383:2030-2040
You see instead of deaths on mechanical ventilation being given directly, it is combined with all deaths into one category. This is called a "composite endpoint" or "composite outcome". So, we need to do the calculation to find the proportion of the ventilated patients who died on HCQ and then calculate the proportion for those not on HCQ who died, since these are not given directly. Use the formula for counting the number of elements in the union of two sets with possible overlap:
which simply means you add together the number in each set, then subtract off the number in the overlap.
What's given in the report is the union of the two sets of the ventilated and of the deaths. But what we want is the intersection, those who were ventilated that died. So we'll turn around that formula for the number in the union to get the number in the intersection as, | A ⋂ B | = |A| + |B| - | A ⋃ B |.
So in this case, |ventilated ⋂ deaths| = |ventilated| + |deaths| - |ventilated ⋃ deaths|. First look at the cases on HCQ. From Table 2, for those on HCQ, |ventilated⋂deaths| = |ventilated| + |deaths| - |ventilated ⋃ deaths| =128+311- 399 = 40. So on HCQ, the rate of deaths on ventilator 40/128 = 0.312, 31.2%.
Now calculate it for the non-HCQ group, i.e., the usual care group. The numbers appear in the "Usual care" column in the table. So in this case, |ventilated ⋂ deaths| = |ventilated| + |deaths| - |ventilated ⋃ deaths|. First look at the cases on HCQ. From Table 2, for those HCQ, |ventilated⋂deaths| = |ventilated| + |deaths| - |ventilated ⋃ deaths| = 225 + 574 - 705 = 94, so the rate of deaths on ventilator is 94/225 = 0.417, or 41.7%. This difference between the number of ventilated patients on HCQ who died of 32.2% and those not on HCQ who died of 42.3% is large enough that it should have been reported.
The RECOVERY trial made headlines world-wide when it sent out a news release on the "breakthrough" that the steroid dexamethasone could cut mortality for ventilated patients by 30%.
Here is the published article on the discovery:
The RECOVERY Collaborative Group
July 17, 2020DOI: 10.1056/NEJMoa2021436
Note that all of the Geleris et al., Rosenberg et al., and the RECOVERY trials could legitimately report that overall there was no statistical difference by using HCQ. But this was because for the important subcase of ventilated patients, their numbers were a small proportion of the total number of cases. However, the large difference using HCQ for that key subcase of ventilated patients should have been reported.
Another instance where positive effects of HCQ were obscured was in a paper by Tang et al. In this case though the positive effects weren't just obscured, they were actually deleted:
Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial
BMJ 2020; 369 doi: https://doi.org/10.1136/bmj.m1849 (Published 14 May 2020)
Tang et al. is regarded as a negative HCQ paper, but deleted from the published version was this passage in the preprint:
"In addition to virus infection, acute inflammation response is another hallmark of COVID-19.19
Recent findings in clinical series have shown that the systemic inflammation or cytokine storm is
the driver of disease progression and death.20,21 Substantially decrease of lymphocyte count and increase of inflammatory response marker, e.g., CRP were both observed in the early stage of patients who eventually progressed and died.21 These results highlighted the importance of the recovery of lymphopenia or anti-inflammation in preventing the development of systemic
inflammation in critically ill COVID-19 patients. Such abilities and benefits were observed from
HCQ in our current trial, showing that patients with SOC plus HCQ had a significantly greater
reduction of CRP level and a moderate elevation of blood lymphocyte count at the last assessment comparing to patients with SOC only. These effects were observed after 5-day of HCQ treatment and maintained until the withdraw of HCQ. These encouraging results suggested clinical benefits of adding HCQ into the current standard management to limit inflammatory response, which is the key to prevent systemic inflammation and subsequent multiple organ failure and death."
The extensive list of benefits of HCQ seen by the Tang et al. research group, that were deleted from the published report was discussed by Dr. Didier Raoult here:
It is extremely unfortunate these details were deleted from the final report. Note this study appeared around the same time as the Geleris et al. and Rosenberg et al. reports in May. Since it shows HCQ effectiveness as an anti-inflammatory, if the Tang published report and the two Geleris and Rosengberg published reports had revealed these positive effects of HCQ, then coupled with the positive results of the Bo Yu et al. report, doctors would have had an effective treatment approach to ventilated patients.
Some Western doctors and researchers may choose to believe the Western studies rather than the Asian studies. But given the fact the death rates in the Asian countries are 1/100th those in the West, I would not be so sanguine about that choice.
As with the antivirals, the Real World Experience approach should be used, with nearby hospitals testing different anti-inflammatories so the comparisons can be made to their effectiveness without confounding factors. And as with the antivirals the comparisons among the various hospitals should be done in real time. And also as with the antivirals the effectiveness of the anti-inflammatories might be seen within days by looking in real-time the presence of the inflammation markers such as IL-6 and CRP, and at the CT scans. The importance of the CT scans is that the improvement in the degree of lung inflammation can literally be seen by the doctors as the treatment progresses:
CT scans can detect coronavirus in patients before RT-PCR lab testing
NEWS | COMPUTED TOMOGRAPHY (CT) | FEBRUARY 26, 2020 | MELINDA TASCHETTA-MILLANE AND DAVE FORNELL
In a study of more than 1,000 patients published in the journal Radiology, chest CT outperformed lab testing in the diagnosis of 2019 novel coronavirus disease (COVID-19)
Chest CT images of a 29-year-old man with fever for 6 days. RT-PCR assay for the SARS-CoV-2 using a swab sample was performed on Feb. 5, 2020, with a positive result. (A column) Normal chest CT with axial and coronal planes was obtained at the onset. (B column) Chest CT with axial and coronal planes shows minimal ground-glass opacities in the bilateral lower lung lobes (yellow arrows). (C column) Chest CT with axial and coronal planes shows increased ground-glass opacities (yellow arrowheads). (D column) Chest CT with axial and coronal planes shows the progression of pneumonia with mixed ground-glass opacities and linear opacities in the subpleural area. (E column) Chest CT with axial and coronal planes shows the absorption of both ground-glass opacities and organizing pneumonia. Image courtesy of Radiology
Rapid identification of COVID-19 severity in CT scans through classification of deep features.
Zekuan Yu, Xiaohu Li, Haitao Sun, Jian Wang, Tongtong Zhao, Hongyi Chen, Yichuan Ma, Shujin Zhu & Zongyu Xie
BioMedical Engineering OnLine volume 19, Article number: 63 (2020)
The observational difference in the appearance of coronavirus inflamed areas of the lung are made apparent in this 3D CT scan:
CT scan shows damaged tissue from a covid-19 patient's lungs.
Apr 1, 2020
Dr. Marcus Chen's research involves making #CT scans safer by reducing the amount of radiation by over 90%. This chest CT shows a stunning view of a #COVID19 patient's lungs. The yellow areas represent normal lung tissue, while the blue areas are damaged tissue. #ImageOfTheWeek
3:12 PM · Aug 5, 2020·Twitter Web App
Department of Mathematics
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