161. Hygia Chronotherapy and COVID-19 with Vitamin D

Get the best evidence because you want to know what they are looking at and occasionally people send me articles I was not aware of. Plus I ate spending my time sending them all the information then people say well ya but you are looking at the wrong evidence just right off the bat say “I will explain but tell me the evidence you are looking at”
So he sent me 5 articles and I going to break them down in hopefully a rapid fire dissection
And before we get started there is a very important piece of information that we all need to be clear on, low vitamin d DOES not mean that replacing the vitamin d then fixes the problem. We knew for a while that high HDL seem to have a protective cardiovascular effect but when we looked at the data it didn’t appear raising the HDL with a drug called niacin had an effect on cardiovascular events. This is the ultimate association and correlation connection. Sure it appears more popsicles consumed are associated with higher rates of drowning but getting rid of popsicles will not get rid of drowning. It appears more car accidents happen within 5 miles of your house and even more car accidents happen within 100 miles from your house but if you get rid of driving within 5 or 100 miles of your house you do not get rid of car accidents so it takes me to the

First article-
https://www.mdpi.com/2072-6643/12/9/2757/htm
In journal of Nutrients titled

Vitamin D Deficiency and Outcome of COVID-19 Patients

This is observational data looking at the associations of vitamin D (VitD) status with disease severity and survival and

Quick take away- Our study demonstrates an association between VitD deficiency and severity/mortality of COVID-19, highlighting the need for interventional studies on VitD supplementation in SARS-CoV-2 infected individuals.


Yes I agree with everything they just said but does replacing the vitamin level with supplements then mean you have a better outcome. This article doesn’t touch on that

Second article-
Also in journal of nutrients titled-

Evidence that Vitamin D Supplementation Could Reduce Risk of Influenza and COVID-19 Infections and Deaths
This is a review article. Review articles are never ever to be used as evidence because the authors have a story they want to tell and they set out to write a paper that tells their story. When you write a review article you never set out with a hypothesis and then you the scientific method to accept or reject the null. You start with a goal in mind and look for papers to confirm your goal. Review articles are the ultimate in confirmation bias. Anytime anyone ever gives you a review article as evidence you should automatically question medicine and politely hand it back to them and say, “thank you but I would prefer something higher than “expert opinion”.

Articles 3- next article was from scientific reports, titled-
https://www.nature.com/articles/s41598-020-77093-z
Analysis of vitamin D level among asymptomatic and critically ill COVID-19 patients and its correlation with inflammatory markers
This was a continuous prospective observational study that look to analyze the vitamin D level in COVID-19 patients and its impact on the disease severity.
Basically they looked at patients vitamin d level during the course of follow up and then used statistical analysis to see if there was an association between vit d levels and severity of illness.
The results found that “vitamin D deficiency (as suggested by serum 25 (OH)D concentration So what they are saying is if you are in the ICU you are more likely to die. They are also saying that those individuals who are sick and in the ICU are more likely to have vit d. deficiency. Wait, you mean I am saying that if you are in the hospital then you have a lower laboratory value that is associated with being outside???? Ya, shocking statement to think of!! This is completely a duh statement, and being admitted to the ICU is also associated with higher rates of intubation. The authors are not saying replacing vit d levels with supplements PREVENTS ICU admission or death.

Next article- https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2770157
In JAMA titled-
Association of Vitamin D Status and Other Clinical Characteristics With COVID-19 Test Results
This is a cohort study that looked to see if vitamin D status was associated with test results for coronavirus disease 2019 (COVID-19)
Remember a cohort study is observational data, they look at people at one point in time and then again at another point in time. They don’t intervene, they don’t treat, they don’t do anything. They look at a point in time called ‘x’ and follow up at a future point in time ‘x’ and see what happens.
This study looked at 500 people who had a vit. D level within the previous year prior to being testing for covid-19 and found that if you had a low vitamin d level you were at 1.8 times greater risk for testing positive for covid-19
This study does not say that if we replaced the vitamin d levels with vit d supplements that then they would have tested neg for covid-19
It really just says if you have a lab value which is already associated with decreased activity and decrease going outside that you are more likely than to test positive for a virus in the next year. Wait, did I just say that if you don’t have a great lifestyle you are more likely to test positive for a virus or get sick from a virus?? Yes that is exactly what I said and I know I am sure this is another shocking finding.


Last article- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456194/
In journal of steroid biochemistry and molecular biology
Effect of calcifediol treatment and best available therapy versus best available therapy on intensive care unit admission and mortality among patients hospitalized for COVID-19: A pilot randomized clinical study”
On the surface this seems like a potentially good study, it even says randomized in the titled, But then you go on to read that this was a randomized open label, double-masked clinical trial.
You think to yourself, wow double masked, that seems like a good thing. The key is who is masked? Because you also know open label is a bad thing because open label means that someone knows exactly what the drug is so that leads to a little bit of bias, if you really want something to work, you will alter your treatment towards that patient based on your own believe. The key is who is masked
This is a problem because the authors wanted this treatment to work and believed this treatment would work and you know how I know this, because they randomized participants in a 2 to 1 fashion. Normally you should enroll people 1:1 it is the most efficient method of randomization from a statistical perspective and requires the fewest number of patients. Enrolling in a 2:1 fashion usually requires about 12% more people to achieve the same level of statistical power.

Now, The reason you make it 2:1 is because you either think that it is easier to enroll patient-subjects in a trial if they believe they are more likely to receive the new/active treatment, or at least that is a reason stated by many authors and experts but this is really only valid when there is clearly one far superior drug from a non-superior drug. There is not enough evidence to say vit d is better than placebo or nothing thus is not valid UNLESS YOU IN YOUR HEART OF HEARTS BELIEF vit d is so much better based on faith and belief and no on evidence.
Another reason to randomize patients 2:1 is a budget issue and one arm of the trial is significantly cheaper BUT that is not the case in this trial because you either got an active drug or nothing. Not an active drug or placebo, it was an active drug or nothing and nothing is free.
Now if you are going to make unequal randomization then you should state why you did it that way. The authors did not. So we will never know the reason they did it.

But I will say the authors believed in vit dand this is easy to see if you know methods of a trial or you can just read the trail and the authors say. “The working hypothesis of this pilot trial was that calcifediol treatment would decrease the need for ICU admissions and the potential risk of death associated with these admissions.”
Said differently “we the authors of this trial have a belief that vitamin d will decrease the need for icu admission and potential risk of death.”

The primary outcomes was rate of ICU admission and deaths
Remember I said this was a “double-masked clinical trial”. The question is, who is masked.”
It is not clear who is masked but it appears the treatment list was “accessible only to non masked specialists in the study”. So some providers in the study had access to who was being treated with vit d. This obviously brings in observation bias and confirmation bias.


So in this study the outcome that showed such a huge benefit was the decrease risk of transfer to the ICU. This is a made up and bs endpoint because it is subjective!! In the paper it says

“A multidisciplinary Selection Committee was created, made up of intensivists, pulmonologists, internists and members of the ethics committee who decided on admission to the ICU.”

So what they are really saying is we have an endpoint for which human error is involved and the individuals who are involved in this outcome or endpoint have access to the information on which group the patient was randomized. So if you know the patient is getting the placebo, you may be a little more likely to transfer them to the ICU than you are if the patient is on vit d. Are you maybe a little more likely to try and treat them on the floor if you know the patient is already getting vit d and you want a positive trial so you can get a publication?? Ya I think so.

Plus they don’t give us the information on the patients transferred vs not transferred to the ICU. Why were they transferred? Did they need intubation? Was it maybe from a low sodium, maybe it wasn’t even covid related. FINALLY—the didn’t factor weight into their final analysis. They didn’t factor in BMI into the rates of severe covid! We know those that have larger bodies are more likely to have a poor outcome in covid and they didn’t include it because they say “ given the isolation characteristics of the patients, we did not collect the BMI,” which is total b.s. in most hospitals you can take a weight on the bed scale. The nurse already has to go into the room to deliver the meds and she or he can't hit one button on the bed to get the results of a bmi.

This paper while may look good just on the service is far far far far far from a slam dunk and between the combination of being open label, randomizing people 2:1, and outcome that is subjective by individuals who may know arm of the trial the patient is in and not including bmi in your analysis there are too many red flags to say this is even useable evidence.

And really this should only be used by attendings to teach students and others how to appraise the medical lit.



In summary- no vitamin d should not be used to prevent or treat covid19 or at least not with the current data I am aware of or have been presented.