As a new disease, evaluation of treatments occurred as emergency rooms were being overwhelmed and desperately looking for ways to keep patients alive. This has resulted in a lot of anecdotal reports. Here are a few laypersons summaries on widely reported double blind studies.
The story of Covid will be how simple science questions can be completely mucked up; bars are fine meeting places,
testing causes cases, convalescent plasma is a breakthrough and worst of all hydrochloroquine. A huge amount of time
and money have been spent chasing hydroxychlorquine. In addition the guidance seems questionable, "It seems to be a
pattern of approval without science, without data, without evidence," said Dr. Eric Topol, vice president for research at
Scripps Research in La Jolla, California and a national expert on the use of data in medical research.
My very simplistic "cliff notes" summary is;
on a ventilator or supportive oxygen - steroids help based on 3 double blind studies
on oxygen - remdesivir helps based on 2 double blind studies
in hospital - vitamin D helps based on 1 small double blind study.
- convalescent plasma is unclear based on 1 observational study
in hospital or before infection - hydroxycloroquine has no benefit based on 4 double blind studies
A small double blind study of Vitamin D on hospitalized patients showed significant reduction in ICU
admissions and deaths 9/7/20
A small study with of 76 consecutive patients hospitalized with COVID-19 infection, a clinical picture of acute respiratory
infection and confirmed virus test. All hospitalized patients received as best available therapy, using hydroxychloroquine
Calcifediol is a metabolite of Vitamin D that is absorbed quickly by the body. Eligible patients were allocated through
electronic randomization on the day of admission to take oral calcifediol, or not. Recommended daily dose of
Vitamin D is 0.025-0.1 mg, the treatment was roughly equivalent to the maximum daily dose.
Patients (50) assigned to calcifediol, 28% were over 60 years old, whereas the control group (26) had 19% over 60, a
statistically insignificant difference, and is close to the Covid infection demographic in the general population.
Results in this small group;
ICU admissions with Vitamin D 2%, control 50% significant at 99.9% confidence.
Fatality of hospital admissions with Vitamin D <2% (no deaths), control 8% .
The control fatality rate for hospital admissions is in line with current experience. Worth noting that all patients received
HCQ plus azithromycin now recognized as causing INCREASED fatality (see below in HCQ summary).
“Conclusion: Our pilot study demonstrated that administration of a high dose of Calcifediol or 25-hydroxyvitamin D, a
main metabolite of vitamin D endocrine system, significantly reduced the need for ICU treatment of patients requiring
hospitalization due to proven COVID-19. Calcifediol seems to be able to reduce severity of the disease, but larger trials
with groups properly matched will be required to show a definitive answer.”
Steroids - dexamethasone & hydrocorizone 9/2/20
The RECOVERY randomized trial being run by the University of Oxford, has reported on 7/17/20 that the steroid
dexamethasone produces statistically significant improvement in mortality for patients on breathing support. Early in the
pandemic it was reported that there were poor outcomes for patients requiring ventilation. There were also anecdotal
reports of success with steroids. .
The report from the RECOVERY trial states that glucocorticoids may modulate inflammation-mediated lung injury and
thereby reduce progression to respiratory failure and death. In the trial a total of 2104 patients the dexamethasone group
had an fatality rate that was lower than that in the usual care group among patients receiving invasive mechanical
ventilation (steroid – control) = -12.1% effect, and among those receiving oxygen without invasive mechanical ventilation
(steroid – control) = -2.9% but not among those who were receiving no respiratory support (steroid – control) = +3.8%.
They concluded that in patients hospitalized with Covid-19, the use of dexamethasone resulted in lower 28-day mortality
among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among
those receiving no respiratory support.
On 2/9/20 3 studies on steroids were published, One was a randomized study on 379 patients (who completed the study)
who were treated with another steroid, hydrocortizone,. The 379 patients receiving intensive care who were treated with
a regular fixed dose of the steroid hydrocortisone for seven days had a better chance of recovery, compared with the
patients who were not treated with the steroid. When the data on dexamethasone above was published, they halted this
study so they did not reach the preset statistical criteria. In the 21 days after treatment, the placebo group had 6 days off
oxygen or ventilator "without organ support", the fixed dose group had 11.5 days without organ support. Their statistical
analysis showed "93% probability of superiority" for the fixed dose hydrocortisone treatment.
The reference concluded "The findings are published in JAMA alongside two further clinical trials which have also
evidenced the benefits of steroids as a treatment for the severely ill COVID-19 patients. This journal edition also includes
an overall analysis of the three independent studies, plus data from the original RECOVERY trial and three other smaller
trials. It concludes that a range of steroids – all safe, cheap and readily available – can improve the outcomes of patients
receiving intensive care."
Back in May, the FDA allowed remdesivir to be used for hospitalized adults who need oxygen, but not those sick enough
to require ventilation, following the publication of a study showing shorter time to recovery using remdesivir.
In this randomized study on patients requiring oxygen as of April 28, 2020, the analysis population included 1059 patients
for whom they had at least some post-baseline data available (538 in the remdesivir group and 521 in the placebo group)
for a fully randomized study. Patients in the remdesivir group had a shorter time to recovery than patients in the placebo
group median, 11 days, as compared with 15 days. Mortality was numerically lower in the remdesivir group than in the
placebo group, but the difference was not significant The estimates of mortality by 14 days were 7.1% and 11.9%
(change of -5%) in the remdesivir and placebo groups, respectively.
In early August, there was a new randomized study of less severely ill hospitalized adults, showing that five days of
treatment with remdesivir was better than standard care, though "the difference was of uncertain clinical importance." In
this randomized, open-label, phase 3 trial that included 584 patients with moderate COVID-19, the day 11 clinical status
distribution was significantly better for those randomized to a 5-day course of remdesivir compared with those
randomized to standard care. The difference for those randomized to a 10-day course compared with standard care was
not significantly different.
The U.S. Food and Drug Administration late Friday allowed the drug remdesivir to be used on all patients hospitalized
with COVID-19, although no published research supports such widespread use.
Time to wade into the hydroxychloroquine (HCQ) mire ! 8/30/2020
A study of studies was published on 8/26/2020 . They found a mind numbing 839 publications on HCQ, that they
selected down using rigor and detail criteria to 29 articles covering 30,000 patients; of which three were gold standard
randomized controlled trials (RCT) or “double blind”. All except 1 study was done on hospital patients. The pooled
change in fatality for the “double blind” studies was (HCQ-control) = +2.3% (HCQ group was worse) ranging from -0.8%
to +6.2%, and for all studies was (HCQ-control) = -4.4% ranging from -9% to +1.5% .
Their conclusion was “Hydroxychloroquine alone was not associated with reduced mortality in hospitalized COVID-19
patients but the combination of hydroxychloroquine and azithromycin significantly increased mortality.”
In addition since this work, there has been double blind study on HCQ on high risk individuals before infection, by U
Minnesota published 8/6/2020. The trial involved 821 high risk participants who had household or occupational exposure
to Covid within 6 feet for more than 10 minutes. Half the participants received relatively high dose of HCQ, and half the
placebo. Within 14 days, 9 of the placebo group had measurable virus. In the same time, 11 of the HCQ group had
measurable virus, obviously no evidence of improvement. The small number of infections means that the difference
between HCQ and placebo are not significant and it was a lot of work for very few usable events.
On 7/16/2020, https://www.medicalnewstoday.com/ today headlined a summary on this and a companion study “HCQ
Flops in Third Randomized COVID Trial; 'Time to Move On' — Trial enrolled outpatients with mild illness, and zinc, vitamin
C were of no help either”
Finally, there has been a recent large (8059 patient) observational study in Belgium. The fatality for the HCQ group was
17.9% compared to 27.1% for the group receiving supportive care a statistically significant (HCQ-control) = – 9%
change in fatality which is consistent with the best study in the study of studies. In observational studies, the test and
control groups are not randomized. In this case, the HCQ group were significantly younger, more male, and in better
health that the group receiving supportive care. The authors used established statistical techniques, but with no details,
to try and correct for these differences and ended to with a -7.4% change. In fact, half of the dead were over 80 years
old, and the supportive group actually had 50% more over 80 year olds compared to the HCQ group. In other words, the
deaths in the Covid group should be multiplied by 1.25. My simple correction based on the over 80’s contribution
suggest a much lower -4.8% change, consistent with the average of study of studies.
What do you think all this tells us ?
Convalescent plasma as potential antibody treatment 8/24/20
The latest buzz is convalescent plasma hailed as “a breakthrough,” by Trump, Azar (HHS) called it “a major advance.”
Hahn (FDA ) “100 people who are sick with COVID-19, 35 would have been saved because of the administration of
plasma.” The inaccuracy of Hahn’s statement left medical experts aghast. Jonathan Reiner of George Washington
University medical school called it “shockingly wrong.” Eric Topol, head of the Scripps Research Translational Institute in
La Jolla, called it “not only blatantly wrong [but] an egregious public statement.”
The pre-review publication is available.
What are we to make of all this hot air? Here is my laypersons take. The data was based on sick people in hospital, 50%
of whom were in the ICU. They tracked the fatality after 1 month of 35,000 patients who received convalescent plasma
at 1800 facilities over 3 months from April through June. Critically, there was no control group to compare to plasma, their
conclusions are based on the differences based on how quickly the patients were treated after diagnosis.
The direct evidence of the effect of plasma on 35,000 patients was that those who were treated 3 days or less after
diagnosis had a 22% fatality, compared to 27% for those treated after 4 days or longer, a change of -5%. Unfortunately,
there was a 2x reduction in the average fatality rate from April to June, as well as large reduction in use of
hydroxychloroquine, and increase in use of Remdesivir. I found the actual change in fatality due to treating with plasma
in 3 days or less compared to more than 4 days, was by month April -4.2%, May -3.7%, June -1.8% ave. -3.3%. Much
less than claimed and possible evidence for the effect of other medications.
There was a more detailed analysis of only 3500 patients sampled over 3 months. In this group they compared fatality
rates to the antibody count in the plasma grouped into low/middle/high levels. The best results for the sub-group treated
within 3 days showed dose- response. The low group (561 patients) had a 1 month fatality of 30% compared to the high
group (515 patients) fatality of 19%, an 11 point improvement. ASSUMING that all the improvement is due convalescent
plasma, only 11 additional people out of 100 survived – Hahn’s claim was indeed “blatantly wrong” – and the real
number is almost certainly smaller.
Within the smaller test population there were still large systematic variations between groups of antibody levels, the high
antibody/lower fatality group had more patients in June, and fewer health risk factors, both of which reduce the apparent
effect of plasma.
My take is that the data suggests that the test group had lower fatality because of EITHER; treatment with high anitibody
plasma, AND/OR fewer heath risk factors, AND/OR more Remdesivir treatments AND/OR less Hydroxychloroquine
treatments, AND/OR general improvements in fatality rates in the general population. There is no way to sort out the
relative contributions based on the published data. As a lay person, I would respectfully suggest that the authors claim
that plasma "significantly reduced mortality" and "several signals consistent with efficacy" are a bit over enthusiastic.
And Hahn's conclusion was not in the paper, so almost certainly he did not read it - he was given a misleading summary
to a inconclusive paper - not good from our supposed health care leaders.
DNA analysis leads to possible mechanism for covid infection and treatments 9/2/20
This is my edit down of the longer reference article.
"Earlier this summer, the Summit supercomputer at Oak Ridge National Lab in Tennessee set about crunching data on
more than 40,000 genes from 17,000 genetic samples in an effort to better understand Covid-19. Jacobson’s team says
in their paper that “the pathology of Covid-19 is likely the result of Bradykinin Storms rather than cytokine storms,” which
had been previously identified in Covid-19 patients, but that “the two may be intricately linked.” Other papers had
previously identified bradykinin storms as a possible cause of Covid-19’s pathologies.
For more on Bradykinin - here is a link to Wikipedia.
According to the team’s findings, a Covid-19 infection generally begins when the virus enters the body through ACE2
receptors in the nose, entering cells in other places where ACE2 is also present: the intestines, kidneys, and heart. But
once Covid-19 has established itself in the body, tricking it into upregulating ACE2 receptors.
Lungs - As bradykinin builds up in the body, it dramatically increases vascular permeability. In short, it makes your blood
vessels leaky. It also increases production of hyaluronic acid (HLA) in the lungs. HLA is often used in soaps and lotions
for its ability to absorb more than 1,000 times its weight in fluid. When it combines with fluid leaking into the lungs, the
results are disastrous: It forms a hydrogel, which can fill the lungs in some patients. Patients can suffocate even while
receiving full breathing support.
ACE inhibitor - By acting like a natural ACE inhibitor, Covid-19 may be causing the same effects that hypertensive
patients sometimes get when they take blood pressure–lowering drugs. ACE inhibitors are known to cause a dry cough
and fatigue, two textbook symptoms of Covid-19. ACE inhibitors are also known to cause a loss of taste and smell.
Toes Leaky vasculature caused by bradykinin storms could be responsible for “Covid toes,” a condition involving
swollen, bruised toes that some Covid-19 patients experience.
Heart - Bradykinin storms could create arrhythmias and low blood pressure,
Brain - According to Jacobson and his team, MRI studies in France revealed that many Covid-19 patients have
evidence of leaky blood vessels in their brains.
On the treatment side.......
There are drugs on the market that target this mechanism -- for hereditary angioedema, a condition marked by
bradykinin overactivation -- and at least two U.S. trials are currently underway. One trial is looking at icatibant (Firazyr) in
critically ill COVID-19 patients, and another is testing lanadelumab (Takhzyro), a monoclonal antibody that targets
kallikrein, in patients hospitalized with COVID-19 and pneumonia.
Vitamin D is a potentially useful Covid-19 drug. This is because vitamin D is one of the very few hormones that regulates
the RAS and prevents bradykinin accumulation. Vitamin D also acts as an immunomodulator that keeps inflammation at
bay. The researchers note that vitamin D has already been shown to help those with Covid-19 (see above).
Hymecromone, for example, could reduce hyaluronic acid levels, potentially stopping deadly hydrogels from forming in
the lungs. And timbetasin could mimic the mechanism that the researchers believe protects women from more severe
All of these potential treatments are speculative, of course, and would need to be studied in a rigorous, controlled
environment before their effectiveness could be determined and they could be used more broadly"