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CHR's COVID-19 Bulletin, April 13, 2020

CHR's COVID-19 Bulletin, April 13, 2020

[This article deals with a rapidly developing situation. It was written by Norbert Gleicher, MD, on April 11, 2020 and published on April 13, 2020. For a list of all COVID-19 Bulletins, scroll to the bottom.]

As expected, death rates from COVID-19 in the New York Tristate Area have reached a peak this week. Quite reassuringly, new hospital admissions and admissions into intensive care have dramatically declined, however. Such declines usually foreshadow similar declines in mortality over the following two weeks. This is, of course, good news but does not yet signal a definite date for the end of this plague. The economic havoc this virus is causing around the world, however, mandates a relatively quick return to more normal economic activities and a public debate on how to accomplish such an “opening” without causing a second wave of COVID-19 infections.

How to interpret what's happened so far

Before one can make plans for the future, one must understand the past: Based on worldwide experiences, there can be no doubt that social distancing, stay-at-home mandates and the substantial shutdown of economic activity employed by most countries have been effective interventions in “flattening the curve.” For quite a number of reasons it is, however, still difficult to assess how effective they have been in doing that: As now has become increasingly apparent, most models build by “experts” at many often very prestigious institutions, proved not only to be false but were exaggerated to almost paradoxical degrees. The most extreme one was probably published by the Royal College in the UK, which was talking about millions of potential deaths worldwide. Some U.S. models were not that extreme but, still, significantly overestimated the severity of the COVID-19 virus and its consequences on the medical system. One, therefore, must ask the question whether decisions made at federal and state levels would have been the same, had original models been more accurate? The likely answer is a pretty decisive no.

CHR's COVID-19 Bulletin, April 13, 2020

The same "experts" have been wrong three times already when it comes to COVID-19. CHR's Dr. Gleicher recommends skepticism.

A second important point is that currently nobody knows what percentage of the population has really been infected. This is not only important in determining the true prevalence of severe medical complications and mortality from this virus, but also for the determination of how high herd immunity toward COVID-19 already is in various communities. The higher the infection rate in a given area, the higher will be the subsequent herd immunity in the community. New York City, based on reports in the media, apparently has demonstrated the highest per-capita infection rate in the country (and maybe in the world). Consequently, it should, going forward, also reap the benefit of the highest herd immunity. And what ultimately stops every viral epidemic as long as there is no vaccine available, is an adequate level of herd immunity. How much the current level of herd immunity has contributed to the drop-off in new infections in NYC is, therefore, currently also unknown, a point that, interestingly, has not at all been discussed in daily briefings from governors around the country and the White House.

What also has not been widely discussed, is the fact that all the above-noted social distancing, stay-at-home mandates and economic shutdowns, while being successful in “flattening of the curve,” did not necessarily reduce _overall _COVID-19 infections. As all graphs depicting the “flattening of the curve” clearly demonstrate, all of these interventions only spread out the infection rates over a longer time period. The purpose of “flattening the curve,” was not necessarily to reduce the number of infected patients but to spread them out, so that infected patients reaching emergency rooms would not overwhelm the intensive care capacities in hospitals. But spreading out infections over a longer time period also means that the herd immunity in the community will take longer to develop and, as a consequence of that fact alone, potentially actually more individuals may get infected with COVID-19 over longer time periods.

We are going in so much detail in explaining all of these moving pieces of the puzzle, in order to explain why the modelling of a viral epidemic is so complex and difficult. Our medical colleagues who specialize in modelling studies, of course, use the concept of modelling pretty much in all areas of medical research. While some of those studies may, indeed, contribute to the literature, clinicians, rightly, are often quite skeptical about the conclusions reached by such studies. Such skepticism is more than warranted because we know how dependent modelling studies are on the assumptions they rely on. Moreover, only too often, models, as in the COVID-19 situation, prove to be significantly off target when followed by clinical investigations.

Within this context, it is also worthwhile noting that the behavioral science literature quite clearly demonstrates how biased “experts” often are in preconceived assumptions which, then, of course, are also reflected in the assumptions that underlie their models. Just as there is a saying in science that, “the right statistical methodology can prove everything,” one, therefore, can also conclude that, “the right assumptions for a model can always produce the desired outcomes.” For that reason, the behavioral science literature warns from automatically trusting “expert” opinions. And on a side note: In the hierarchy of scientific evidence, the prospectively randomized trial is universally considered the gold standard; guess what represents the absolutely lowest level of evidence? You were right if you guessed that this honor goes to “expert opinions.”

Regarding COVID-19, “experts” were pathetically wrong in their predictions not only once but at least twice: In the beginning when first reports came out of China and Taiwan, they clearly underestimated the threat of the virus. Yet just a few weeks later, exactly the same experts, finally recognizing the seriousness of COVID-19, compensated for their earlier underestimates by exaggerating the viruses’ future threats. As behavioral scientists will tell you, such compensatory behavior is not uncommon and actually quite typical. It, of course, is not done with intent but happens subconsciously. If further misjudgments are to be avoided, scientists, and those who listen to them, should, however, be aware of this very obvious weakness in our thinking/behavior and be appropriately cautious with “expert” opinions. Evolution has, fortunately, given us herd immunity, but unfortunately, it has also given us “herd-thinking,” best defined as a process where a few leading “experts” agree on a course of action and, automatically, the herd follows. Considering that “expert” opinions are at the very bottom of the evidentiary hierarchy, this appears like a rather peculiar way of reaching important policy decisions. And big decisions are awaiting us, if the U.S. economy is to recover as quickly and as safely as is possible.

The ridiculous controversy about hydroxychloroquine (Plaquenil)?

How removed “expert” opinion from reality can be in the midst of this crisis is also well demonstrated by the ridiculous discussion that has now for weeks been consuming media, medical experts, pundits, politicians and even the president: It is all about a drug, called hydroxychloroquine, sold under the brand name Plaquenil. This medication has been clinically and safely used at very low costs by millions of individuals, initially as the first seriously effective and preventative medication against malaria and, more recently, as a mainstay in rheumatology, especially in patients with systemic lupus erythematosus (SLE). CHR has been using Plaquenil for ages as an anti-inflammatory agent in women with elevated inflammatory markers and repeat miscarriages. The reason why CHR started using this drug routinely was, indeed, its well-established safety profile in pregnancy. Our rheumatology colleagues have been using the medication during pregnancy in SLE patients for decades.

First reports that the drug may be effective against Corona viruses surfaced during the 2002-2004 severe acute respiratory syndrome (SARS) outbreak, like COVID-19, a Corona virus that first appeared in China.

Not surprisingly, Chinese colleagues started using the medication when confronted with COVID-19 and reported surprisingly good results. Considering the severity and the urgency in treating severely affected patients, studies were, however, not prospectively randomized (the highest level of evidence). One, indeed, could argue that randomization in giving patients this medication (which means half of the patients would get placebo, an ineffective sugar pill), would be ethically inappropriate. But the studies the Chinese colleagues reported were also not of the lowest level of evidence (that, as mentioned above, is the “expert” opinion). As so-called cohort studies, these studies from China, followed very quickly by those from a number of other places around the world, suggested that hydroxychloroquine, in many patients, indeed, could make a significant difference. A relatively high level of evidence that this drug, likely, does have a significant effect against COVID-19 came also from laboratory investigations that not only confirmed that the drug killed COVID-19 virus in the dish but also discovered the process by which the drug did the killing.

This is when President Trump made the costly mistake of advocating for the use of the drug in COVID-19 cases. Within this context, it is also important to mention that the same president just a few months earlier signed a law that radically opened the access of terminal cancer patients to experimental pharmaceutical drugs before they received an FDA approval (“right to choose”). His “right to choose” rationale was the same: If people are dying and we do not have any approved treatments that work, why not use something like hydroxychloroquine (Plaquenil) that may work? Moreover, in contrast to most experimental cancer medications, nobody has to worry about the safety profile of hydroxychloroquine or its costs because it has been used in millions of men and women with practically zero side effects and costs only pennies.

But this is when the same “experts” again came into the picture and, even though most of them never practiced clinical medicine or, maybe, exactly for that reason, they came out against use of the medication until prospective randomized clinical trials would be conducted and reported. Following their logic, roughly 85 percent of all clinical practice in the U.S. should immediately stop because, as studies have demonstrated, only less than about 15% of current medical practice in Western medicine is based on prospectively randomized studies. The rest of medicine is all based on lower levels of evidence, like, for example, cohort studies, or even the lowest evidence, namely “expert opinions,” like the recent ones by our COVID-19 “experts” that suggests that hydroxychloroquine should not be used in COVID-19 patients.

But there is an even better argument made for use of hydroxychloroquine in the current COVID-19 epidemic and that is that, basically, every hospital and every intensive care unit that treats severe COVID-19 patients is using the medication already. A reproductive endocrinologist from another fertility center, who as a resident spent some time at CHR, unfortunately ended up for days in intensive care at one of the leading university hospitals in the city with an extremely severe case of COVID-19. He and many other professionals we know and have had conversations with are convinced that _Plaquenil _saved their lives. All, indeed, report surprisingly quick improvements in their condition after start of the medication.

As we are writing these words, we don’t know whether this, indeed, is the case. We really, indeed, don’t know for sure whether this medication saves lives because to be certain one, indeed, must conduct prospectively randomized studies. But, as long as there is not a proven alternative drug available, why not use it? The time to perform a randomized study of Plaquenil is not now; That time will come once an alternative drug has been approved by the FDA for use against COVID-19, because, then, deadly sick patients at least don’t have to take the risk of getting a placebo of sugar pills. Randomization can be done between both treatment options and the question will be which one of the two drugs works better.

That “experts,” who the President of the U.S. and the country are listening to, do not have the common sense to understand all of this, is seriously troubling and not only because those same “experts” are now wrong for the third time in a row on very important issues. One, therefore, must wonder how likely it is that they will be correct on the next big issue coming down the road, the “reopening” of the country?

We recommend skepticism!

CHR's COVID-19 Bulletins

Norbert Gleicher, MD

Norbert Gleicher, MD, FACOG, FACS

Norbert Gleicher, MD, leads CHR’s clinical and research efforts as Medical Director and Chief Scientist. A world-renowned specialist in reproductive endocrinology, Dr. Gleicher has published hundreds of peer-reviewed papers and lectured globally while keeping an active clinical career focused on ovarian aging, immunological issues and other difficult cases of infertility.

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