Ibuprofen and COVID-19 (Are NSAIDs Safe_), Trials of HIV Medications, Preliminary CDC Fatality Data (Lecture 40)
Welcome to another MedCram covid-19 update. We’ve got a lot of news to cover today. There have been a lot of things that have come back from a medical standpoint. There were over 200,000 total confirmed cases worldwide; total deaths almost 9,000; total recovered 84,000.
If we look country by country on the WorldOmeter site, we can see here only 34 new cases total in China at this point. Most of the cases are outside of China. In fact, more cases in Italy in terms of active cases than there is anywhere else in the world at this point. The United States cases have jumped to almost 10,000. That’s probably because of increased testing that is now coming online in the United States. Despite that, we only have about 64 serious or critical cases in the United States out of a total of 9200.
We also have news here from the CDC. In their morbidity and mortality weekly report that was released yesterday on March 18, it says that the first preliminary description of the outcomes among patients with covid-19 from the United States indicates that the fatality was highest in persons greater than 85 years of age, ranging from ten to twenty-seven percent; followed by three to eleven percent mortality among persons aged 65 to 84; one to three percent mortality among persons 55 to 64; less than one percent among persons 20 to 54 years of age, and no fatalities among persons less than 19 years of age.
Here, we see the number of new covid-19 cases reported daily in the United States from February 12 to March 16, and you can see that that has gone up steadily, and here you can see it by age group how many hospitalizations in the light lavender and ICU admissions in the darker blue, and then deaths in the darkest blue. You can see that there is a stepwise increase here in different ages.
For the greater than 85 years of age, there were more deaths than there were in the intensive care. That may be because of palliative care or hospice, where you have patients that are hospitalized but never go into the Intensive Care Unit before they pass. Here is the breakdown for age groups here in terms of hospitalization percentage, ICU admission percentage, and case fatality percentage.
This is the big news that was published today in the New England Journal of Medicine. It was the trial of lopinavir and ritonavir, which are HIV medications in hospitalized adult patients with severe covid-19. This was a trial that was done in China. This was a trial that was a randomized controlled, open-label trial because they couldn’t have time to prepare the placebo pills, and they gave it to randomize patients, of course, to see how they would improve with covid-19.
The endpoint here was either discharged from the hospital or an improvement on a seven-point scale, which we’ll talk about. The primary endpoint was the time to clinical improvement defined as the time from randomization to an improvement of two points on a seven category ordinal scale, or live discharged from the hospital, whichever came first.
The seven-point scale has been used before in other influenza studies. This is the scale. I: If you’re not hospitalized with resumption of normal activities; 2: if not hospitalized, but unable to resume normal activities; 3: hospitalized, not requiring supplemental oxygen; 4: hospitalized, requiring supplemental oxygen; 5: hospitalized, requiring nasal high-flow oxygen therapy, non-invasive mechanical ventilation, or both; 6. Hospitalized requiring ECMO, invasive mechanical ventilation, or both; and 7: death. If there was a movement down of two points, or a discharge from the hospital, that would indicate improvement.
七分制以前曾在其他流感研究中使用过。这是衡量标准。1：如果您没有因恢复正常活动而住院； 2：如果未住院，但无法恢复正常活动； 3：住院，不需要补充氧气； 4：住院，需要补充氧气; 5：住院，需要鼻高流量氧疗，无创机械通气或两者兼而有之； 6.需要ECMO和/或有创机械通气的医院； 7：死亡。如果下降了两点，或者出院了，则表明情况有所改善。
You have 357 participants that were assessed for eligibility. There were some that dropped out, leaving a hundred and ninety-nine, which underwent randomization, and you had 99 that were assigned to the intervention group, which was lopinavir and ritonavir, and a hundred that were assigned to the standard care group.
Like any good studies should do, they show you what the two groups were, and what their characteristics were. If you look up and down the lopinavir and ritonavir category, and the standard care, there really wasn’t much difference between them at all statistically, which means that the randomization was pretty good.
If you look at these, you can kind of get a sense about who these patients were, the median age in both of these was 58. There was a majority of males here, which we’ve seen before. Body temperature interestingly was not febrile.
In terms of the median, 36.5 is not a fever; in terms of those that had a fever, we had 89 percent and 93%. We had a number of people that had respirations above 24, those who had a systolic blood pressure of less than 90 notice were a very very small percentage of people. So most of these peoples’ blood pressures are actually elevated.
The other thing that was interesting to note here is that the amount of people with relatively low white blood cells is pretty extensive. So typically this is what you’re going to see, and you can look at the other characteristics. When you look at the types of interventions that were done, you can see again pretty much similar going up and down the categories.
Let’s take a look at the results. Again, here we’ve got days on the x-axis, and we have the cumulative improvement rate that we see in greater than 2 points. So if this is working well, we should see that these things go up rather quickly. In fact, what we see here is that while there is some space between the lopinavir and the ritonavir, it is not statistically significant. So it turns out that this is a negative study. It did not show a difference between the lopinavir and ritonavir, and the control group, at least in these pretty severe hospitalized patients.
You can see here in terms of the viral load, which should be coming down very nicely over time. Again, no real difference between the intervention of lopinavir and ritonavir group and the control group.
So the authors drew this conclusion: in hospitalized adult patients with severe covid-19, no benefit was observed with lopinavir and ritonavir treatment beyond standard care.
There’s been a number of questions about NSAIDs. The recent issue in terms of the French Minister saying that we should not use NSAIDs in covid-19. There’s also this really good summary of the key points that were put out by a pharmacist organization in Canada, which I will put a link to in the description below. The summary also goes through the salient points about the possible risks and benefits of NSAIDs in covid-19.
But let’s talk a little bit about what NSAID is and what it has to do with viruses. So NSAIDs stand for non-steroidal anti-inflammatory drugs. For a long time, the thing that reduced inflammation was steroids. So these were a new category of medications that were not steroids, but they could reduce inflammation. Probably the earliest one that was invented was aspirin back in 1899. More on that one later. very importantly.
We’ll talk though about Ibuprofen. Ibuprofen is probably one of the most widely used NSAID in the world, and it’s used to reduce inflammation, reduce fever. It’s used for osteoarthritis, a number of indications for NSAIDs.
NSAIDs among other things have a special impact on an enzyme that we’re going to talk about, which is cox2. Cox2 stands for cyclooxygenase-2 as opposed to cyclooxygenase-1, which it also can inhibit, but that’s not really germane to our discussion.
What does Cox2 do? It takes a substance called arachidonic acid, which will abbreviate AA, and it converts it into prostaglandins, specifically PGE2. Now coxswain also makes thromboxane, and that is used in platelets, but that’s not really germane to what we’re talking about.
What we want to look at here is the cox-2 enzyme, which converts arachidonic acid into prostaglandin E2 now. Why is that important? Because prostaglandin E2 is involved with pain, which is why we would give it. It’s also involved with fever, which you would see in a viral infection, but it’s also involved in antibody production, or more specifically, cox-2 is involved in antibody production.
What NSAIDs do to that is they halt it. They prevent it. Antibodies are important; antibodies are made by B cells, and B cells make these antibodies to go out into the serum and attack things that should not be there; things like viruses.
So you could see why NSAIDs may cause a problem. Yes while they get rid of pain and fever, they can also hit your antibody production, but NSAIDs specifically ibuprofen and to a lesser extent other NSAIDs as well. They also have another function because they also inhibit some other things they could apparently can inhibit viral replication, and it’s been shown to hit the SARS-COV, not 2 but the original, the one that was from 2002.
It’s also been shown to attack the canine version of coronavirus, and it’s also been shown to be toxic and inhibitory to both influenza A and B. So the question is which one is it doing more and you can see why there might be benefits on either side and risks on either side.
What do we do? This pharmaceutical organization that put out this statement from Canada that was prepared a couple of days ago. They say here further research including randomized controlled trials is required to determine the impact of NSAIDS on coronavirus infection and subsequent disease.
They go on to talk about confounding variables. The NSAIDs could be treating comorbid conditions which put them at increased risk of more severe covid-19 disease. And so the bottom line is you need a randomized controlled trial. So I think the answer at this point
Is we don’t know based on this data. So then I did something really weird. I went back in time to an epidemic of a viral illness that was a pandemic and at the time they actually had an NSAID and it was given quite liberally and so the question is what happened at that time and what were the observations and it actually is really quite interesting.
And here’s a paper that was published in 2009 salicylates and pandemic influenza mortality 1918 to 1919 pharmacology pathology and historic evidence, and we’ll put a link to this as well in the description below and what it talks about is that aspirin at just come out in 1899, and it was a fresh drug to be used at the time. It was great way to get rid of fever and some people thought that if you could just treat the symptoms.
Terms of the flu the patient would get better and one of the big symptoms of the flu, of course was the fever the paper goes into discussing what the toxic dosages are today based on what we know at the time people would be given large doses of aspirin until they saw toxicity. Then they would sort of pull back they talk about four lines of evidence support the role of salicylate intoxication in 1918 influenza mortality, the pharmacokinetics the mechanism of action pathology and the fish.
Social recommendations for toxic regimens of aspirin immediately before the October 1918 deaths bike for those who don’t know one grain equals 65 milligrams. So when we talk about Grange, you’ll see the Aspen regimens recommended in 1918 are now known to regularly produce toxicities and you can read about that here. We do know that salicylates cause immediate lung toxicity and may predispose to bacterial infection by increasing lung fluid and protein levels and Imperial mucociliary clearance.
Lawrence and at the pathology of early deaths that we saw back in 1918 was consistent with Aspirin toxicity and a virus induced pathology and remember aspirin which is a salicylate is also an NSAID. So this kind of makes an interesting Twist on the discussion about whether we should be using NSAIDs in covid-19, and then interestingly its talks about the aspirin advertisements in August of nineteen eighteen and a series official recommendations for aspirin in September early, October.
Preceded the desk bike of October 1918 and it’s interesting that the young adults coming back from World War 1. We’re more likely they felt to take aspirin. Whereas the lower mortality in younger children may have been the result of less aspirin use and interestingly the major pediatric text of the time in 1918. And remember they have no antibiotics. They have no antivirals. They have no ventilators essentially what would happen in a major surge recommended not ask?
And not salicylate but actually recommended hydrotherapy for fever. These were the great thinkers working with what they had at that time and we can see at the time that there was a dichotomy that was set up in the treatment of the Spanish Flu back in the 1918-1919 those that really believed in the pharmacodynamics and pharmacokinetics of aspirin and those that would treat with hydrotherapy. This is dr. William a Pearson in
18 I’m quote. None are so blind as those who cannot see that the average mortality of influenza patients treated by homeopathic Physicians was actually only about 130th and that’s a 30 not 13th, but one thirtieth of the average mortality reported by all Physicians and then Dr. C J lezail from Des Moines in 1999 says the German aspirin has killed more people than the German bullets have
So the question boils down to what are we getting in terms of risk benefits of these NSAIDs and ibuprofen or even aspirin are we confounding the mortality of 1918 with the dose of aspirin some would say yes is this just a larger magnitude of the effect that we might be seeing with NSAIDs with covid-19. I think it Bears testing. I think at this point we don’t have enough answers for that. I would say though that in my research of the night.
In 18 Spanish flu epidemic and pandemic. I think there are some parallels that we might be able to learn from because if in fact we do have a surge in this country, like what we are having in Italy the question is going to be what was it that worked back in 1918 and can we learn anything from there? Because we may very well be in a similar situation if we don’t have ventilators as they didn’t have if we don’t have pharmacological interventions as
as they didn’t have back then we don’t have antivirals as they didn’t have back then and don’t have antibiotics. In other words. Is there some lesson that we can learn from them that we could apply in our own homes for instance to improve survival. I think that bears thought and deserves research. Thanks for joining us.