April 11, 2020

Jacob Schor, ND, FABNO

“Falsehood flies, and truth comes limping after it, so that when men come to be undeceived, it is too late; the jest is over, and the tale hath had its effect: like a man, who hath thought of a good repartee when the discourse is changed, or the company parted; or like a physician, who hath found out an infallible medicine, after the patient is dead.”

Jonathan Swift, The Examiner. No. XIV (Thursday, November 9th, 1710)

I began writing this piece in early March, still in the early days of social distancing brought on by efforts to limit harm brought by the Covid-19 virus.  The normalcy of the recent past was still fresh in memory and the uncertainty of what life would bring in the near future is so vague that it was hard to fathom. We were still acting as if our plans for the future were intact.  The momentum of our lives still pushing us forward toward a reality that no longer exists. If and when this article gets published, we will be living in a far different world than we can conceive of today.  

There were several studies that we were pondering at the time, studies whose implications may be less relevant then we first thought; but the lesson comes from how we responded to those studies rather than their conclusions.

In early March, two articles were published about Covid-19 and ACE2 binding sites that reached opposite conclusions.  The first, written by David Gurwitz, was published March 4, 2020 in Drug Development Research. [i]  The second, a letter from Lei Fang, George Karakiulakis, and Michael Roth written to the editor of Lancet Respiratory Medicine, was published online March 11, 2020.[ii]Both the article and the letter looked at similar information about the Covid-19 virus and how it binds to ACE2 sites and reached opposite conclusions.  

Early mortality data had suggested (and continues to suggest) that patients with certain comorbidities, especially diabetes, high blood pressure, and cardiovascular disease, are at greater risk of dying from this infection than those without such conditions.  Fang and colleagues point out that these patients, “… are often treated with angiotensin converting enzyme (ACE) inhibitors.” 

Both point out that Covid-19 binds onto angiotensin-converting enzyme 2 (ACE2) located on its target cells.  ACE2 is the doorknob that allows the virus to enter cells.  Patients with diabetes make more ACE2 receptors than people without diabetes.  Treating their blood pressure with ACE inhibitor drugs increases ACE2 levels even more.  Thus, Fang and colleagues theorized that taking ACE inhibitor drugs could increase risk, severity and mortality from infection from these viruses. 

Gurwitz suggested that, although admittedly ‘counterintuitive’, these same drugs could be protective, and that rather than trying to lower ACE2 expression, we might want to instead increase it: “… while seemingly paradoxical, [doing so] may protect them against acute lung injury rather than putting them at higher risk to develop SARS. This may be accounted for by two complementary mechanisms: blocking the excessive angiotensin-mediated AT1R activation caused by the viral infection, as well as upregulating ACE2, thereby reducing angiotensin production by ACE and increasing the production of the vasodilator angiotensin.”

These papers each present a hypothesis that was the opposite of the other.  (A hypothesis, by the way, is, ‘a supposition or proposed explanation made on the basis of limited evidence as a starting point for further investigation.’ So really a hypothesis is just a guess based on inadequate information.)  

Gurwitz suggested data mining as the next step to test his idea, that is analyze already existing patient records to see if those patients taking ACE inhibitors fared better than others. 

The idea that ACE inhibitors should be avoided spread rapidly on the internet and via news outlets.  At the same time, because certain anti-inflammatory drugs, like ibuprofen, increase ACE2 levels, there was widespread warnings that they too would worsen the disease.

Fang’s hypothesis spurred the idea that NSAIDs would aggravate Covid-19 infections and make them more lethal.  This theory took off on March 3; France’s Health Minister Olivier Veran, tweeted… that “taking anti-inflammatory drugs (ibuprofen, cortisone…) could be an aggravating factor of the infection. If you have a fever, take paracetamol. If you are already on anti-inflammatory drugs or in doubt, ask your doctor for advice.” [iii]

France sent out an official alert that same day saying much the same thing,  that there are reports that:  “grave adverse effects” linked to the use of non-steroidal anti-inflammatory drugs (NSAID) — the family of drugs that includes ibuprofen — have “been identified with patients affected by Covid-19, in potential or confirmed cases.”  “We repeat that the treatment of a fever or of pain linked to Covid-19 or to any other respiratory viral disease should be paracetamol [Tylenol].” [iv]  That French warning quickly went international or, more appropriately, it went viral.  

Cautious people wondered if there was evidence and found none.  On March 17, 2020, Gina Kolata, writing in the NY Times, was still seeking evidence supporting Olivier Veran’s tweet.   [Kolata’s article did contain a description of the role fever plays in fighting infection, a description that is so reminiscent of Dr. Anna MacIntosh’s Physiology Class lectures on the subject 30 years ago at NCNM, that my eyes teared up as I read it.][v]  

The idea that NSAIDS may worsen Covid-19 infection, whether extrapolated from Fang’s unconfirmed hypothesis, or not, will only be confirmed true or false if and when human data are published.  We cannot make judgement calls based on a weak hypothesis. 

Yet why did we all hear about this NSAID business while hardly anyone heard the idea that ACE inhibiting drugs or, by extension NSAIDs, might be good for patients with Covid-19?  Why did one of two competing theories become widespread while the other was ignored? Reading the original articles now, it is Gurwitz who presented the more cogent argument.  One possible answer was published in the journal Science, almost two years to the day, in fact, before the Fang and Gurwitz’s articles were published.

On March 9, 2018, Science published a massive study on fake news.  The study’s authors had analyzed every major contested news story broadcast on Twitter over a ten-year period.  Their database included 126,000 stories, tweeted by 3 million users.  They concluded that hoaxes and rumors consistently win out over the truth. In every way measured, false ideas beat the truth: fake news reached more people, penetrated deeper into the social network, and spread faster than accurate stories.  Now Fang’s hypothesis wasn’t exactly fake news but it shared a characteristic with most fake news stories, it had an incendiary element to it.  

[By the way, Robinson Meyer wrote an excellent piece on that fake news study for The Atlantic that I recommend to anyone interested in this.[vi]]

“It seems to be pretty clear [from our study] that false information outperforms true information,” said Soroush Vosoughi, a data scientist at MIT who led the Science study. “… It might have something to do with human nature.”

On the same day as Science published Vosoughi’s data, they also published a plea from more than a dozen scholars calling for a new drive of interdisciplinary research “to reduce the spread of fake news and to address the underlying pathologies it has revealed.”  They asked, “How can we create a news ecosystem … that values and promotes truth?”[vii]

Although Vosoughi analyzed data only from Twitter, there is little reason to think Facebook, YouTube or other platforms are any more honest. As Meyer wrote in The Atlantic, 

“Any platform that regularly amplifies engaging or provocative content runs the risk of amplifying fake news along with it….  A false story reaches 1,500 people six times quicker, on average, than a true story does. And while false stories outperform the truth on every subject—including business, terrorism and war, science and technology, and entertainment—fake news about politics regularly does best…. Twitter users seem almost to prefer sharing falsehoods. Even when the researchers controlled for every difference between the accounts originating rumors—like whether that person had more followers or was verified—falsehoods were still 70 percent more likely to get retweeted than accurate news.”

“Why does falsehood do so well? The MIT team settled on two hypotheses.

“First, fake news [viii] seems to be more “novel” than real news. 

“Second, fake news evokes much more emotion than the average tweet. … Fake tweets tended to elicit words associated with surprise and disgust, while accurate tweets summoned words associated with sadness and trust, they found.” [ix]

Paul Herscu shared his own theory about this with me.  He wrote me via email: “I think fake news and quick whatevers fit into the same bin as candy, ice cream and pizza. It satisfies something primal. ….. I kind of hope that reason wins out in the end, but that didn’t really help Orpheus in the midst of the maenads[x].”

This is not to say that Fang’s hypothesis was fake news.  One might wonder whether Minister Veran’s Tweets were fake or just well-meant mistakes.  The answer would depend on how we define fake news.  Does fake news require an element of maliciousness and ill intent?  Or can we generate fake news innocently?  Whatever the case, the emotions provoked by Veran’s inaccurate warning triggered a viral spread similar to how purposefully generated fake news travels.

By the time you read this article, we may already know whether ACE inhibitors are good or bad for Covid-19 patients.  In fact, two studies were published the first week of May that seem to put the matter to rest.

A paper published May 1 in the New England Journal of Medicine, written by Harmony Reynolds et al., suggests neither theory is true.  Reynolds’ group identified all the patients in the New York University (NYU) Langone Health electronic health record who were tested for Covid-19 test from March 1 to April 15, 2020.    Of these 12,594 patients, 5894 (46.8%) were positive; 1002 of these patients (17.0%) had severe illness. “There was no association between any single medication class and an increased likelihood of a positive test. None of the medications examined was associated with a substantial increase in the risk of severe illness among patients who tested positive.” [xi]  

A week earlier, on April 23, 2020, JAMA Cardiology published a study by Chinese researchers on patients in Wuhan, China that reached similar conclusions.  They had looked at 1178 patients with COVID-19, of which 362 patients had hypertension (30.7% of the total) and of these, 115 (31.8%) were taking ACEI/ARBs. The in-hospital mortality in the patients with hypertension was 21.3%. The percentage of patients with hypertension taking ACEIs/ARBs did not differ between those with severe and non-severe infections (nor did it differ between non-survivors and survivors. [xii]  So far ACE inhibitors do not appear to make a significant difference.

By the time you read this, we may know whether social distancing was an adequate measure to control this pandemic based on increasing or decreasing human fatalities. We may know a lot more about how to deal with this virus.  Yet we are unlikely to have found a fix for the tendency for lies and falsehoods to spread quicker and more extensively through human social networks than the truth.  This may be the greater danger moving forward.

Hippocrates called upon physicians to practice ‘rational medicine’ and because of that exhortation, we have an obligation to favor true information and call out and discredit false information. Yet how do we do it?

There is no magic formula that allows us to segregate truth from falsehood.  In my boomer naivety I asked Google for instructions on how to tell true from fake news.  I ended up with multiple lists to help guess whether a story is fake or not.  Harvard lists 4 criteria [xiii],  the International Federation of Library Associations (IFLA) lists eight [xiv], NPR lists five [xv]. None are guaranteed and all leave one to make the judgement on your own.

What we all need is an App that will check statements or better yet an old-fashioned divining rod that will bend toward the truth.

Given what is at stake and what a threat fake news has become, I think it is important that we, as professionals,  make an extraordinary effort to set an example for our patients and colleagues; we must go above and beyond the ordinary when disseminating ideas and be explicitly clear about the sources underlying our statements of fact, clearly identifying ideas that are under debate and to be unbiased and objective in our analysis of competing ideas.  People learn by example and we can no longer add credibility to our argument by writing, “studies say this is true.”  We need to accurately cite supporting studies and also those studies must accurately confirm our statements.

[i] Gurwitz D. Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics. Drug Dev Res. 2020 Mar 4. 

[ii] https://www.thelancet.com/pdfs/journals/lanres/PIIS2213-2600(20)30116-8.pdf

Lancet Respir Med 2020 Published Online March 11, 2020 

[iii] https://www.cnn.com/2020/03/16/health/coronavirus-ibuprofen-french-health-minister-scn-intl-scli/index.html

[iv] https://dgs-urgent.sante.gouv.fr/dgsurgent/inter/detailsMessageBuilder.do?id=30500&cmd=visualiserMessage

[v] Kolsta G.Is Ibuprofen Really Risky for Coronavirus Patients? NY Times. March 17, 2020

[vi] Meyer, R. The Grim Conclusions of the Largest-Ever Study of Fake News. The Atlantic. 3/8/2018


[vii] Lazer DM, Baum MA, Benkler, Y et al. The science of fake news, Science.  09 Mar 2018:

Vol. 359, Issue 6380, pp. 1094-1096

[viii] In the few years since this study was published, even the term “fake news” has taken on a new but inaccurate meaning, distorted to refer to reports from the news media that paint a negative picture of the president, whether they are accurate reporting or not.  For the sake of clarity, I will continue to use the academic definition of “false information or propaganda published under the guise of being authentic news.”

[ix]  https://science.sciencemag.org/content/359/6380/1146

[x] In Greek mythology, maenads were the female followers of Dionysus, often portrayed as in a state of ecstatic frenzy, dressed in fawn skins and carrying a thyrsus (a long staff wrapped in ivy and tipped with a pinecone.)  I can’t help but wonder that Dr. Herscu’s choice of this reference might have to do with his new office being located a short walk from Smith College.

[xi]  Reynolds HR, Adhikari S1, Pulgarin C1, et al.  Renin-Angiotensin-Aldosterone System Inhibitors and Risk of Covid-19.  N Engl J Med. 2020 May 1. 


[xii] Li J, Wang X, Chen J, Zhang H, Deng A. Association of Renin-Angiotensin System Inhibitors With Severity or Risk of Death in Patients With Hypertension Hospitalized for Coronavirus Disease 2019 (COVID-19) Infection in Wuhan, China.  JAMA Cardiol. 2020 Apr 23. 

[xiii] https://www.summer.harvard.edu/inside-summer/4-tips-spotting-fake-news-story

[xiv] https://www.ifla.org/about

[xv] https://www.npr.org/2019/10/29/774541010/fake-news-is-scary-heres-how-to-spot-misinformation