I have read many social media posts during the COVID-19 pandemic by people that claim to be frustrated and confused with scientists. They say that first it was “masks are not necessary” and now it’s “wear masks”. First millions were projected to die, and then tens of thousands. A test for COVID-19 is put out, but then it doesn’t work. Articles are published showing hydroxychloroquine is dangerous and clinical trials are paused, but then then the articles are retracted, and the trials are continued. Hydroxychloroquine is authorized to be used, and now no. These people claim that they are tired of flip-flops, dithering, and mistakes. Some are even arguing that these happenstances are not random, and that they represent a pattern which is part of a conspiracy by scientists aligned with pharmaceutical companies, the left, the World Health Organization, and the Gates Foundation to scare US citizens, impose on them, deprive them of cheap effective therapies, and take away their freedoms. The above reaction is not unexpected. We know that belief in conspiracy theories greatly increases in times of social upheaval that generate uncertainty, stress, and anxiety. But apart from that, a lot of the exasperation and confusion some people have with scientists and the scientific process stems from unrealistic expectations regarding what science is, what scientists do, and how they do it, coupled to the realities of doing research in the current environment. So let me set the record straight. The history of science is awash in stories where scientists have made mistakes, flip-flopped on theories, and retracted articles in their pursuit of truth. Some of these mistakes occurred because of faulty data, technology, or procedures, and other mistakes involved scientists having wrong ideas. Normally scientists have time to sort out all these mistakes and methodological issues over the course of a few years (or in some cases decades), and they can come up with a reasonably robust approximation to the truth. This is a messy process with a lot of uncertainty, missteps, and blind alleys, but most of the time this process happens away from the limelight. When most folk come into contact with scientific discovery, what they see is the end product of this process, the tip of the iceberg if you will, and they are usually oblivious to all the blood sweat and tears that has taken to get there.
So, take this scientific process with all of its imperfections, mistakes, and uncertainties, and put it in the middle of a pandemic where people are dying and society needs answers, tests, therapies, and guidelines, NOW! You have just rushed the scientific process tenfold, and you have also magnified the potential for screw-ups by the same amount. Add to this the fact that COVID-19 research, from vaccines to hydroxychloroquine, has been politicized, and that every relevant announcement is interpreted in favor or against something and amplified orders of magnitude by the news cycle and social media. Finally, factor in that the general public is being exposed on a daily basis to the process of science in this difficult environment but often filtered through the sieves of partisan pundits that distort the science. What do you get? What you get is one sad toxic mess. Very preliminary or questionable research is catapulted to the forefront of public attention and presented as the truth, whereas solid research is nit-picked to find flaws in order to dismiss it. Honest mistakes or changes of opinion by scientists are interpreted in the worst possible way to question the trustworthiness of the individuals involved. Many excellent scientists doing what they’ve always done the way they’ve always done it are now portrayed at best as Keystone Cops or at worst as sinister characters of questionable morals whose motives behind their actions are divorced from the well-being of the public. No wonder some people are frustrated and confused with science and scientists! But my message to these people is the following: Don’t concentrate on the PROCESS of science. Focus on the PROGRESS of science. Progress? Yes, progress! Science and scientists have made an immense amount of progress during the COVID-19 pandemic. Scientists have isolated and sequenced the genetic material of the virus and generated a huge amount of information that has been used (among other things) to produce vaccines that are being tested for safety and efficacy, to identify strains of the virus which allow us to trace its spread, to generate diagnostic tests to detect viral infection in individuals, and even to detect the virus in sewage in order to identify which communities may have a rising caseload! At no time in the history of infectious diseases has progress happened so fast. Contrary to what was initially believed, scientists have discovered that the SARS-CoV-2 virus (which causes the disease COVID-19) can infect many cell types once it has gained access to the body through the airways, including those of the lining of blood vessels, and this has changed the way we view the disease, saving and improving the lives of patients. For example, one of the problems with seriously sick patients is blood clots, and the use of anticoagulants is helping to save lives. Scientists have also tested several drugs against COVID-19, and have found steroids to be effective at reducing mortality in the sickest patients. Other approaches that may also be useful, and are being tested, are the drug remdesivir and convalescent plasma. After being ambivalent with regards to masks, scientists discovered that a large amount of COVID-19 transmission occurs from people that are asymptomatic or presymptomatic. This discovery led to the issuing of the guideline to wear masks, which along with social distancing and other mitigation measures have bought us time to better understand the virus and saved lives. At the level of the hospitals, doctors integrated domestic and international experiences to develop better ways of preparing for a surge in hospitalizations to handle large amounts of patients. They also recognized that delaying ventilation and placing patients on ventilation in the prone position could improve their odds of surviving. The PROCESS of science can be messy and confusing, and now that it is out in the open on a daily basis, it is being presented to the general public in the worst possible light by many people interested in disavowing science or pursuing their own agendas. When it comes to science, try to understand that scientists are human. They have disagreements, they make mistakes, and they change their minds. You may not understand all the technical terms and issues and all the back and forth among scientists and what’s true and what isn’t. But the PROGRESS of science is a different matter. Science has delivered for us in the past, science is delivering for us now, and science will continue to deliver for us in the future. Concentrate on the end result, on what scientists have achieved. Progress over Process! Progress sign by Nick Youngson from Alpha Stock Images was modified and is used here under an Attribution-ShareAlike 3.0 Unported (CC BY-SA 3.0) license. Coronavirus image by Alissa Eckert, MS; Dan Higgins, MAM, from the CDC's Public Health Image Library is in the public domain and was modified.
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8/20/2020 Hydroxychloroquine: There are Arguments and Counterarguments, but You Can't Have it Both WaysRead NowI have had several exchanges with the folks that argue that hydroxychloroquine (HCQ) is an effective treatment for COVID-19, and in this post I want to go over some of the arguments and counterarguments that have been bouncing around the internet, and try to make sense of them within a logical framework. Other posters and I have pointed out to the HCQ proponents that the best-designed studies have not found any effects of HCQ administered alone or with antibiotics (1, 2, 3, 4, 5, 6,and 7). In response to this, the HCQ proponents argue that these studies used HCQ doses that were too high and even (they claim) toxic for the study participants. Some HCQ proponents have suggested that these high doses were administered on purpose to make the HCQ groups in the studies fail, and they infer a nefarious purpose behind this, such as the study authors selling out to Big Pharma to discredit a cheap treatment for COVID-19 (HCQ) in favor of vastly more expensive treatments. Why did these studies use these high doses? There was nothing nefarious about choosing those high doses. It was done according to scientific rationales based on mathematical models that incorporate parameters such as the absorption, distribution, metabolism, and excretion of HCQ, and its activity against the virus in cell culture, coupled to the understanding that administering a short course of HCQ for a viral infection (which requires rapid drug penetration into tissues for effective prompt antiviral activity), is different from dosing HCQ for chronic conditions like rheumatoid arthritis or lupus. Specifically, not only is HCQ a weak antiviral, but HCQ has what is called a large volume of distribution. This is a pharmacokinetic parameter that describes the amount of a drug present in plasma in relation to the amount present in the rest of the body. Drugs (such as HCQ) with a high volume of distribution take longer to reach therapeutic concentrations in the blood, and require a loading dose to quickly reach the therapeutic concentration, followed by maintenance doses to sustain these therapeutic concentrations.
The dosing in these studies was carefully engineered based on knowledge of known toxicity of chloroquine overdoses and other considerations to achieve high HCQ concentrations while minimizing toxic side-effects. The high doses actually favored HCQ. If these studies had used the low doses that HCQ proponents advocate in social media, the studies would have been open to the criticism that the doses the studies used were not high enough for HCQ to be effective! I want to also dispel the notion that HCQ is being shot down because it is a cheap therapy from which Big Pharma will not profit. One of the trials that did not find an effect of HCQ, the Recovery Trial, did find an effect of steroids in reducing mortality for patients with COVID-19 receiving respiratory support, and steroids are generic cheap medicines which are now being used successfully to save the lives of COVID-19 patients. If Big Pharma could control the outcome of the HCQ arm of the study, why would it allow the steroid arm of the trial to succeed depriving them of millions of dollars they could have earned with their expensive therapies? Make no mistake: If HCQ alone or with antibiotics had been found to be effective, we would have seen it in the Recovery trial and the rest of similarly well-designed clinical trials. Further evidence against HCQ as a single agent that I’ve mentioned before, includes: 1) People who suffer from lupus and were taking HCQ when the pandemic started, were not protected from COVID-19 compared to those lupus patients that were not taking HCQ, and 2) HCQ does not protect macaque monkeys or hamsters against COVID-19. Additionally, as I have also mentioned before, HCQ has been found to have no antiviral action in cells from the human airways, which is probably due to the inability of HCQ to block a specific pathway of viral entry into these cells. Under the massive weight of the evidence some of the HCQ proponents have reluctantly admitted that HCQ alone does not work against COVID-19, but they claim that this is irrelevant because HCQ was not coadministered with zinc. The so called “zinc hypothesis” of HCQ action states that it is zinc that has the antiviral action (it prevents replication of the virus), and that the role of HCQ is to facilitate the entry of zinc into the cells. HCQ proponents claim that the clinical trials using HCQ alone are silly because HCQ is being used in a fashion that won’t be effective (i.e. without zinc). All the clinical trials I mentioned above with HCQ as a single agent or with antibiotics, but no zinc, were designed and commenced in the early phase of the pandemic when zinc was not part of the argument. The initial trials that brought HCQ to the attention of the world and the initial hypothesis of HCQ action did not involve zinc. Scientists were testing the hypothesis that was current at the time. This is perfectly reasonable and understandable. However, at least one clinical trial did analyze a subset of patients who were taking zinc supplements (scroll down to table S8) and found that this did not make a difference in the treatment outcome. But because this was not part of the treatment of the formal study protocol, this result is not conclusive. There are several ongoing clinical trials that include hydroxychloroquine and zinc, so we are waiting for those results to decide if the combination of HCQ and zinc works Finally, I need to address an issue that I have seen played out over and over in social media. HCQ proponents dismiss again and again any HCQ trial that does not combine the drug with zinc, but at the same time cheer and defend the results of trials that find a positive effect for HCQ even if it was not used with zinc, such as the one from Dr. Raoult’s lab or the one from the Henry Ford Health System. And when these trials are criticized for having biases that compromise their interpretation (which they do: big time), HCQ proponents lash out at the critics and insult them calling them stooges of the establishment who have sold out to Big Pharma interests that want to shoot down HCQ even if it kills tens of thousands of Americans. If HCQ does not have an antiviral activity of its own and just acts as a facilitator for zinc to enter the cell and stop viral replication (like the zinc hypothesis proposes), then trials that use HCQ alone SHOULD NOT work. You can, of course, argue that other effects of HCQ besides getting zinc in can produce some positive results, but they would certainly be far from stellar. The fact that trials such as the one from Dr. Raoult’s lab or the Henry Ford Health System found impressive results with HCQ alone actually raises a huge red flag, because they indicate the extent of the biases that compromised the interpretation of the results. This is why we can’t rely on observational studies like these to come to meaningful conclusions. My message to HCQ proponents is that science is about discriminating between alternative hypotheses. If you argue that the best trials found no effect because you need to administer HCQ with zinc in order for the therapy to work, you can’t argue at the same time that HCQ has great effects on its own. You can’t have it both ways. Yin Yang Image by Gregory Maxwell and the image of hydroxychloroquine by Fvasconcellos are in the public domain and were modified 8/8/2020 Cultured Cells, Dr. Fauci, and a Bold Hypothesis to Explain Why Hydroxychloroquine Alone Doesn't Work for COVID-19Read NowHow did the notion arise that hydroxychloroquine could be used against the SARS-CoV-2 virus that causes COVID-19? I want to spend some time on this because it involves an article that is often quoted to slander Dr. Fauci. In 2005 there was a study where chloroquine (a drug related to hydroxychloroquine) was found to be effective at reducing infection with the virus, SARS-CoV (which is 79% related to the COVID-19 virus, SARS-Cov-2), in primate cells in culture. Early on in the COVID-19 pandemic, it was claimed that Dr. Fauci was lying when he said that there was no good evidence for the effectiveness of hydroxychloroquine against COVID-19 because he has known about this article for 15 years. This claim is still being made over and over in social media, and has even been retweeted by some high profile people in the hydroxychloroquine debate. Any scientist who has worked with cells in culture (for example, me) will tell you that extrapolating from cultured cells to the full organism is fraught with peril. The metabolism of cells in culture and the way they react to chemicals or biologicals can be substantially different from the way they react as part of the full organism. In the full organism, cells are in a three dimensional matrix, interacting with other cells types and exposed to the daily cycles of fluctuations in levels of nutrients, hormones, temperature, oxygen, etc. Also, any drugs delivered to the organism, depending on the mode of delivery, may have to pass through several layers of other cells before they reach their intended target. In culture, the cells are in a two dimensional environment interacting only with cells like themselves under fixed conditions. When you deliver a drug to the cells in culture, it reaches them right away. So, more often than not, what you get using cell culture, is different from what you get in the full organism. Additionally, the cells used in the study mentioned above were Vero E6 cells. This is a cell line derived from the kidney of an African Green Monkey, and these cells even have a different number of chromosomes compared to those of the original monkey. Infecting cultured cells from the kidney (not the airways) of a monkey (that are different from human cells and even from the cells of the original monkey) with the SARS-Cov virus (which is different from the COVID-19 virus), treating them with chloroquine (which is different from hydroxychloroquine), and then extrapolating the results to the full human being to argue that Dr. Fauci “…has known for 15 years that chloroquine and it’s even milder derivative hydroxychloroquine (HCQ) will not only treat a current case of coronavirus (“therapeutic”) but prevent future cases (“prophylactic”).” is scientifically inaccurate, to say the least. Then why do scientists use these monkey cells to test compounds against viruses that infect humans? The answer is that these cells can be infected with many viruses and they are a convenient, but very preliminary, test that can be used to screen many compounds quickly, and identify those that display activity against viruses. Once a compound is identified, it is subjected to more complex tests that may involve human cells and studies with whole animals to see if it still works. As it turns out, hydroxychloroquine has been recently been tested with these Vero E6 cells, and it has been found to have antiviral activity against the SARS-CoV-2 virus. But can hydroxychloroquine stop the COVID-19 virus from infecting cells from the human airway, which is the main site of entry of the virus into the body? A study performed with reconstituted airway epithelium developed from primary human nasal or bronchial cells indicated that hydroxychloroquine had no activity against the COVID-19 virus. Why would this be the case? A group of researchers have proposssed a very clever answer to this question. There are two ways that the COVID-19 virus can get into a cell. One involves the uptake of the virus into an intracellular compartment called the “endosome”. The endosome is a compartment that is acidic which is optimal for the functioning of an enzyme called Cathepsin L (CatL) that acts on the virus and activates it. One of the effects of hydroxychloroquine is to lower the acidity of the endosome which impairs the activity of CatL and thus hinders the activation of the virus. However, the cells of the human airway epithelium have low levels of CatL. In these cells, the entrance of the virus is achieved through a second route involving activation by an enzyme called TMPRSS2 which is not dependent of endosomes or acidity and is therefore not affected by hydroxychloroquine. Thus the CatL (hydroxychloroquine sensitive) pathway is predominant in Vero E6 cells, whereas the TMPRSS2 (hydroxychloroquine insensitive) pathway is predominant in the human lung cells. If you use Vero E6 cells that have been genetically engineered to express the TMPRSS2 enzyme (and thus have the TMPRSS2 pathway too), then hydroxychloroquine loses its ability to inhibit the COVID-19 virus infection of the cells! Other researchers have also found that the inhibition of SARS-CoV-2 entry into cells by hydroxychloroquine is antagonized by the presence of the TMPRSS2 pathway. The above is a bold hypothesis that explains why hydroxychloroquine alone has not been found to work in the best-designed studies (1, 2, 3, 4, 5, 6, 7) performed so far. The reasoning is that it does not work because it doesn’t affect the TMPRSS2 pathway of COVID-19 virus activation that is the predominant viral activation pathway in human airway cells! This hypothesis also eliminates the original rationale to use hydroxychloroquine, which arose from using Vero E6 cells as a screen, and it shows how wise Dr. Fauci was in not giving a lot of importance to that very preliminary 2005 study. Nevertheless, notice I mentioned that the above proposal is just a hypothesis. Some people have interpreted the results to mean that hydroxychloroquine reduces the COVID-19 viral infection in monkeys, not humans. However, hydroxychloroquine does not reduce or prevent COVID-19 infection in macaque monkeys. More studies are needed before we can conclude that this is the reason why hydroxychloroquine doesn’t work in humans. However, if you are one of the people that argue that hydroxychloroquine by itself is not active (has no antiviral activity), but rather that it enhances the uptake of zinc which has the real antiviral action, then this hypothesis does not affect your claim. Whether zinc acts with hydroxychloroquine to ameliorate or prevent COVID-19 remains to be demonstrated in well-designed clinical trials (and several are ongoing). But what we can say right now is that the best evidence we have so far indicates that hydroxychloroquine IS NOT effective by itself or with antibiotics against COVID-19, and it’s time we started accepting this. Micrograph of Vero Cells under green light (100X) by Y tambe is used here under an Attribution-Share Alike 3.0 Unported license. This micrograph was merged with an image of hydroxychloroquine by Fvasconcellos which is the public domain. As I wrote before, it is unfortunate that the president of the United States has endorsed the use of hydroxychloroquine against COVID-19, because this has politicized everything having to do with the perception of this drug by the public. When scientists or non-scientists think about hydroxychloroquine, they should be thinking about it as “a drug” that we are researching to find out whether it’s beneficial against COVID-19. Unfortunately, as I warned before, this is becoming more and more difficult. Now hydroxychloroquine is “the president’s drug”. In the current social mindset if you think hydroxychloroquine works, then some people believe you are for the president and for promoting and using a worthless drug, and if you think hydroxychloroquine doesn’t work, some people believe you are against the president and against saving thousands of lives using a drug that has been proven to work. Any statement about the drug is viewed through these warped lenses. In my exchanges on Twitter, I often encounter individuals who promote many erroneous or ambiguous claims about hydroxychloroquine. I have stated, for example, that we can’t rely on the opinions and experiences of doctors and patients to establish whether the drug works. We need clinical trials. I try to explain that doctors, patients, and all human beings in general including scientists are prone to biases that arise through no fault of their own, and that is why we have procedures such as blind protocols and placebos to guard against these biases. However, my comment is invariably interpreted to mean that I am questioning the qualifications of hundreds of doctors, and the trustworthiness of thousands of patients, because I want to discredit positive results for hydroxychloroquine.
I have also tried to explain that not all clinical trials are well-designed. Just because some trials found that hydroxychloroquine works, that doesn’t mean it works. Just because some trials found that hydroxychloroquine doesn’t work, that doesn’t mean it doesn’t. Scientists have to evaluate the quality of the trials. All clinical trials have limitations, which we have to take into account before we make a decision. The results of one well-designed clinical trial can trump hundreds of poorly designed trials. However, my comments regarding the hydroxychloroquine clinical trials are invariably interpreted to mean that I am trying to discredit the studies that favor the drug because of ulterior motives. As I have stated before, I am a hydroxychloroquine skeptic, but my skepticism towards the drug is not rooted in a desire to shoot it down just because the president promoted it. My skepticism is based on well-designed published studies, soon to be published studies, and reviews that indicate that hydroxychloroquine as a single agent or combined with antibiotics is not effective to treat patients sick with COVID-19 or as a prophylactic to prevent patients from being infected with COVID-19 or at least ameliorating their disease. Below are some of these studies: Reviews Efficacy of Chloroquine or Hydroxychloroquine in COVID-19 Patients: A Systematic Review and Meta-Analysis Update I. A systematic review on the efficacy and safety of chloroquine/hydroxychloroquine for COVID-19 Studies A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19 Effect of Hydroxychloroquine in Hospitalized Patients with COVID-19: Preliminary results from a multi-centre, randomized, controlled trial A Cluster-Randomized Trial of Hydroxychloroquine as Prevention of Covid-19 Transmission and Disease Hydroxychloroquine in Nonhospitalized Adults With Early COVID-19 Hydroxychloroquine for Early Treatment of Adults with Mild Covid-19: A Randomized-Controlled Trial Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19 Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial In addition to the above, the hydroxychloroquine trials at the World Health Organization (Solidarity trial) and the NIH (Orchid trial) were halted when independent reviewers of the data concluded that hydroxychloroquine offered no benefits (these trials have not yet been published).. Early on in the pandemic, the narrative was put forward that patients with Lupus who were taking hydroxychloroquine were less affected, or did not develop COVID-19 with the same severity. But this is not true. Lupus patients on hydroxychloroquine get COVID-19 at rates and severity comparable to Lupus patients not taking hydroxychloroquine. Baseline use of hydroxychloroquine in systemic lupus erythematosus does not preclude SARS-CoV-2 infection and severe COVID-19 Finally, there are also studies with animals that have shown no effects of hydroxychloroquine. Hydroxychloroquine Proves Ineffective in Hamsters and Macaques Infected with SARS-CoV-2 Hydroxychloroquine use against SARS-CoV-2 infection in non-human primates Back in 2005, some observations on the effectiveness of chloroquine were made in an experiment performed in culture on a cell line derived from the kidneys of an African Green Monkey (Vero E6 cells). The results of this experiment have been used nowadays to try to discredit Dr. Fauci. In the article that I quoted above on testing hydroxychloroquine on non-human primates, the authors tested hydroxychloroquine on Vero E6 cells and found that it has an antiviral effect. Then they tried the drug on a model of reconstituted human airway epithelium developed from primary nasal or bronchial cells (a more relevant model) and they found that hydroxychloroquine has no antiviral effect, whereas previously the authors had found that remdesivir did have an antiviral effect in this model. Based on some of the above evidence the FDA revoked its emergency use authorization of hydroxychloroquine. Like I have said many times, all studies have limitations, and it’s healthy to discuss the strengths and weaknesses of studies. But in their comments, many of the apologists of hydroxychloroquine go beyond this, as they infer a nefarious intent behind the limitations of the studies, which they assume to have been introduced into the study protocol on purpose to make hydroxychloroquine (and the president) look bad. If these people have very good evidence that this is the case, then they should present it, otherwise engaging in this innuendo is unwarranted, disrespectful, and unacceptable. Even though I am skeptical of hydroxychloroquine, I don’t want to be right, I want to save lives. If well-designed clinical trials prove that hydroxychloroquine works, then it works, and we HAVE to accept it works; no excuses. However, if well-designed clinical trials prove that hydroxychloroquine doesn’t work, then it doesn’t work, and we HAVE to accept it doesn’t work; no excuses. Whether the president promoted the drug or whether the results of the studies agree with your politics is irrelevant. This is what science is, or at least should be about. Hydroxychloroquine should just be “another drug” being evaluated for COVID-19 by scientists having the best interests of the patients in mind. Hydroxychloroquine should not be “the president’s drug”. Making it the president’s drug fans the biases and prevents a rational appraisal of whether it works or not. Note: after I published this, it was pointed out to me that hydroxychloroquine may work when combined with zinc. I have acknowledged that to establish this we need to wait for the results of several clinical trials that are ongoing. However, the subject of this post is the original claim that was made for hydroxychloroquine: that it works as a single agent or combined with antibiotics. Sure, we will move on to zinc, but first can we agree that the evidence from the best studies indicates that hydroxychloroquine as a single agent or combined with antibiotics DOES NOT work against COVID-19? The photo of President Trump from Whitehouse.gov is in the public domain. This photo was merged with an image of hydroxychloroquine by Fvasconcellos also in the public domain. There is a lot of ignorance, misinformation, and conspiracy theories being spread about wearing masks during the COVID-19 pandemic, and I thought I would devote a post in my blog to set the record straight and provide references. Here I want to clarify that by “masks” I am referring to the regular loose fitting surgical or cloth masks that most people normally wear. For my post, I will describe the things people argue about masks and then reply to each one. When you buy the masks that many people use, it says on the box that they won’t protect the wearer from the coronavirus. Many doctors and scientists say that surgical or cloth masks worn by most people will not prevent them from getting the virus. This is an aspect of mask wearing that is not well understood by the general public and even by quite a few scientists, so I will try to explain. Masks got a bad rap back in 1918 when they were considered to have failed in controlling the spread of influenza, and a lot of this thinking still prevails in the scientific community today. However, it has been understood that the wearing of masks back then was often not performed adequately and was not coupled effectively with other measures. The type of masks most people wear will only provide limited protection from breathing in droplets (inward direction) emitted by unmasked people when they are talking, coughing, or sneezing within a short distance of the wearer (less than 6 feet). But that IS NOT the point of wearing these masks. The point of wearing these masks is to contribute to PROTECT OTHERS from the droplets emitted by the wearer when talking, coughing, or sneezing, in other words, to stop droplets in the outward direction (this is referred to as “source control”). There is abundant evidence that these masks can do this, not perfectly, but fairly well (1, 2, 3, 4, 5, 6, 7). You can find some fun demonstrations of the effectiveness of masks here, here, and here. Additionally, taking into account that we now know that many individuals with COVID-19 can transmit the virus even while they are presymptomatic or asymptomatic, mask wearing by the public is even more important to protect others. However, if others do not wear a mask in your presence, this defeats the purpose of wearing masks. The point of wearing a mask is to minimize the chance that the wearer will contaminate others. Nevertheless, it must be emphasized that the intention is for masks to be worn in addition to social distancing, hand washing, and avoiding or minimizing your exposure to crowded places. Doing ALL these greatly decreases your probability of catching the virus. The virus is tiny, it will not be stopped by face masks with large fabric holes like the ones most people wear. Wearing a cloth mask to stop the virus is like putting up a chain link fence to stop mosquitoes.
Yes it will be stopped, because viral particles are expelled forming part of liquid droplets, and the majority of these droplets are hundreds to thousands of times larger than the virus. The mask stops or deflects a significant proportion of these droplets. Cloth masks will trap all the germs like bacteria, viruses, and fungi you expel and then you will breathe them back in and this is bad for your health. That is kind of the point of wearing masks: to trap the germs! This is why you should wash cloth masks after you use them. You put on clean clothes before you begin your day, right? Well, also put on a clean mask. How hard is that? Wearing a mask will trap carbon dioxide and you will breathe back all that carbon dioxide which will decrease your oxygen levels and harm you. This has been demonstrated by performing carbon dioxide measurements inside the masks while people are wearing them. If you (wrongly) argue that it is impossible to trap the COVID-19 virus with a cloth mask because it is so small, then you can’t argue at the same time that the mask will trap carbon dioxide. Carbon dioxide is a gas. A molecule of carbon dioxide is hundreds of times smaller than the COVID-19 virus and tens of thousands of times smaller than the liquid droplets which contain the virus. The social media notion that masks trap carbon dioxide arose as a result of a video posted by a person who used a measuring device improperly and obtained bogus measurements. This notion is inaccurate as the space between the mask and the face is very small and makes a negligible contribution to the dead volume of the lungs. With each inhalation the gas in this space is replaced by gas from the outside. In any case, the appropriate measurement to perform is whether the oxygen levels in the blood decrease as a result of wearing a mask. A number of health care professionals have done this and posted the results on social media. Masks don’t decrease blood oxygen levels. In many Asian countries huge numbers of people have worn masks during the cold and flu season for decades without any such problem arising. The real purpose of a mask is to serve as a mind control device by a manipulative government that wants to roll back our freedoms and make us afraid and submissive. This is a conspiracy theory, and it is up to their proponents to present evidence that it is true. An alternative explanation is that our elected representatives are just following the best evidence and facts available as relayed to them by science. But the argument portraying masks as a mind control device can be made about virtually anything. Use of seat belts, stopping at traffic lights, following speed limits, using a cross walk to cross the street, and many other safety guidelines or laws can all be interpreted as things or designs dreamed up by the powers that be to control our lives and reduce us to sheep. If we accept this, then any government action that involves requesting a change in the behavior of the population can then be assigned a nefarious motive becoming part of a conspiracy. People have fought against masks before and now they are doing it again. We know to a certain extent why people are fighting face masks and promoting conspiracy theories about them even while coronavirus cases, hospitalizations, and deaths are on the rise. It is a combination of the anxiety and loss of control that a situation like COVID-19 produces, the politicization of the issue, and the distrust of government many individuals profess coupled with the erosion of the trust in science that has taken place in our society. However, as I’ve written before, reality can’t be compromised. The evidence so far indicates that masks, when coupled to social distancing and other measures, contribute to decrease the spread of COVID-19. It is our job as scientists to uphold these facts. Many people will not like this. However the point of science is not to win popularity contests but to discover and convey the truth. And we are going to keep on doing just that. The image from the Centers for Disease Control and Prevention is in the public domain. 7/3/2020 Fighting Coronavirus Misinformation and Conspiracy Theories: Fauci, Hydroxychloroquine, and Retracted ArticlesRead NowOh dear, so much COVID-19 misinformation, and conspiracy theories, and so little time and space. Let’s get started. Dr. Anthony Fauci is receiving a lot of criticism from people, ranging from those who deny the severity of COVID-19 and think he misadvised the president, promoting the interests of political elites and the deep state, to those who think he is denying the efficacy of hydroxychloroquine and promoting the economic interests of pharmaceutical companies to the detriment of the interests of patients. These people question his character, and call him a liar, a fraud, a traitor, and a saboteur who should be fired. As it turns out, these insults are nothing compared to the insults levied against him when he was coordinating the nation’s response to the AIDS epidemic in the 1980s. The notorious firebrand AIDS activist Larry Kramer criticized Dr. Fauci for moving too slowly in finding a treatment for AIDS, and said he was evil and represented a callous government. Kramer called Fauci a pill-pushing tool of the medical establishment, an incompetent idiot, a disgrace, and a murderer who should be put in front of a firing squad. Kramer compared him to a Nazi and even insulted Fauci’s wife! So what did Dr. Fauci do? He talked to Kramer and other AIDS activists, he heard their concerns, he realized they had a point, and he pushed for changes in the way clinical trials were conducted speeding up the process, making it more flexible, and giving patients a greater voice. He reached out to those who insulted him and worked with them to change medicine for the better and make history. Eventually, Dr. Fauci and Kramer became good friends. Fauci helped Kramer get medical treatment for his health problems, and Kramer made Fauci a character in one of his award winning plays. So when critics say Dr. Fauci doesn’t care for patients or is beholden to special interests, I am skeptical of these claims. I think that history so far indicates that this is not who Dr. Fauci is. This is not to say that Fauci doesn’t make mistakes, but I certainly believe that he is acting in the best interest of the American people. But can’t people change? Sure, but as far as I’m concerned, the burden of proof is on the critics to produce exceptional evidence that there is a nefarious intent behind his actions. Another conspiracy theory involving Dr. Fauci states that he has known for 15 years that chloroquine (a drug related to hydroxychloroquine) was effective in hindering the spread of a virus, SARS-CoV, which is 79% related to the COVID-19 virus (SARS-CoV-2), in primate cells in culture based on a study published back in 2005. So it is claimed that Fauci is lying when he says that there is no good evidence for the effectiveness of hydroxychloroquine against COVID-19. Dr. Fauci is a competent scientist, and he knows that cell culture is a very preliminary step when employed to look for effective drugs. He knows that the results obtained with this method may not hold in more complete models that better reflect the complexity of the full organism. For example, hydroxychloroquine did not have either a therapeutic or prophylactic effect in hamsters and monkeys infected with the COVID-19 virus. This agrees with the best human studies so far that indicate that hydroxychloroquine is not effective. Another conspiracy theory that is making the rounds concerns retracted articles published in the scientific journals, The Lancet, and the New England Journal of Medicine (NEJM). These two journals published studies where scientists examined a database of patients treated with hydroxychloroquine and concluded not only that hydroxychloroquine was not effective, but that it was also harmful to the patients. The results of these studies led to a temporary halt of several hydroxychloroquine trials taking place worldwide. However, when the studies were examined by scientists, numerous discrepancies in the data and problems in its analysis were detected. Letters signed by more than one hundred scientists were delivered to the Lancet and to the NEJM outlining these problems. The journals expressed concerns about these discrepancies, and the authors of the articles retracted them when they were not able to dispel these concerns with the company that provided them with the hydroxychloroquine dataset. The conspiracy argument alleges that the publication of these articles proves that there is a concerted campaign by the scientific establishment to discredit hydroxychloroquine at the expense of the lives of people who could benefit from it, just to embarrass president Trump for advocating the use of this drug. The conspiracy theory argues that this scandal demonstrates that scientists have lost all credibility. However, what this argument ignores is that it was scientists who detected these problems and alerted the journals, and the journals proceeded to raise concerns with the authors, and the authors acknowledged those concerns and retracted the articles when they could not address said concerns. That this happened is not a scandal. Scientists make mistakes all the time. In fact, that is the strength of science. The only reason that science can be right is because it can be wrong. In this case, error was detected, addressed, and removed. The scandal would have been if the problems with the articles had not been addressed and the articles had not been retracted. The fact that the opposite happened is an indication that science worked the way it should, and vindicates our confidence in the scientific process. Finally, another conspiracy theory involves the claim that countries that have embraced the use of hydroxychloroquine are doing better than countries that haven’t. Therefore, the unwarranted rejection of hydroxychloroquine by the health care systems of some countries has led to many preventable deaths. Those that espouse this conspiracy theory do not make any efforts to address other variables that could explain these differences. For example, there is the number of infected people that spread the disease initially in the country (more disease spreaders equals more infections and more problems with the health care system). There is the timing of the spread of the disease (earlier spread means less time to adapt). There is the constellation of drugs and procedures that are used to treat patients (how do you separate the effect of hydroxychloroquine from that of other drugs and/or procedures). There is the age and health of the population affected (younger healthier people are less susceptible). There is the strength and effectiveness of the mitigation measures employed (older sicker people could have been protected better in one country than in another another). There are differences in reporting what constitutes a COVID-19 death from one country to another. If these and other variables are not considered and controlled for, the claim does not go beyond a mere anecdote. The misinformation and conspiracy theories I’ve mentioned are but a fraction of all the bilge that’s out there, but what they all have in common is that they are part of an effort to disqualify mainstream science and scientists as they deal with COVID-19 and evaluate hydroxychloroquine and other drugs. The image of Dr. Fauci ny NIAID is used here under an Attribution 2.0 Generic (CC BY 2.0) license. The image of hydroxychloroquine by Fvasconcellos is in the public domain. I had an exchange on Twitter with people alleging that doctors are finding that the drug hydroxychloroquine is 100% effective against COVID-19 and posting videos of patients claiming they had been cured by this drug. I tried to explain that this evidence is not valid and provided a link to one of my previous posts that addressed these claims. Then I stated that we need to wait for the results of the clinical trials. The response I got was that if doctors and their patients have tried it and are convinced it works, then that’s all the evidence we need. Unfortunately, this is simply not true. Even before hydroxychloroquine came along, the majority of patients hospitalized with COVID-19 would survive. If all patients are treated with hydroxychloroquine, then how do we know which patients got better because of the drug and which got better because they were going to get better anyway, or because of other treatments? In an uncontrolled clinical environment in the middle of a pandemic, patients are not randomized into matched groups and their treatments controlled and blinded to exclude placebo effects and other biases. Patient testimonials and doctor’s opinions are valuable to design clinical trials, but they have many shortcomings and should never be used to establish whether a drug works or not. All doctors know (or should know) this. However, the main point of this post is not to address the claim that hydroxychloroquine is 100% effective against COVID-19, but rather the attitude of scientists towards such claims, especially when they are reported using the media instead of the regular scientific channels. Scientists know that products or therapies that are 100% effective are rare, and this is even more so in the case of major diseases like COVID-19. Some vaccines, hormones like insulin, or a few antibiotics have approached this level of effectiveness, but this is not very common for most other compounds or drugs. About 86% of the drugs tested in clinical trials are found not to be effective and are not approved. Claims of 100% efficacy for a drug or therapy will trigger a strong (and warranted) skeptical response from most scientists. I have been around a while, and I have read many investigations into multiple bogus claims regarding miracle cures or procedures promoted by quacks. One of the characteristics of these individuals is that they inflate the claims they make regarding the efficacy of their products or therapies beyond the bounds of credibility. If these fraudsters wanted to be believable, they would probably look up the percentage cure rate of the best science-sanctioned therapy and then inflate the claims for their products or therapies by a few percentage points to make them look significantly better but not impossibly so. However, the target audience of these individuals is not scientists but the general public, which has no experience with scientific research or clinical trials and their nuances. As I have explained before, the best way to promote a bogus product or therapy is to make your audience assimilate your product as part of their identity. If you can achieve this, your audience will be impervious to evidence that the product does not work. This is because any attack on your product will be viewed by the members of your audience as a personal attack on themselves. From this vantage point, it is unfortunate that the president of the United States has promoted the use of hydroxychloroquine. In the current politically charged atmosphere, I am concerned that this identity-forming process seems to be coalescing around the notion that if you don’t accept that hydroxychloroquine works, then you are against the president and thus part of a left-wing conspiracy. It is then all too easy for unscrupulous individuals to exploit this situation by linking themselves to the “pro-president” audience and peddle hydroxychloroquine or other as yet unproven drugs or therapies for COVID-19. If their claims are questioned, all they have to do is argue they are being attacked by the same system that their audience believes is against them and the president. I was skeptical about hydroxychloroquine from the beginning, not because the president promoted it, but because the data for its effectiveness was weak. Thus when I hear these claims for 100% effectiveness of hydroxychloroquine (or any other drug or therapy for that matter), this immediately raises a red flag, and I close my mind to them. This may not seem the scientific thing to do, but remember that keeping your mind too open can be dangerous. As far as I’m concerned, like the late astronomer Carl Sagan said, “Extraordinary claims require extraordinary evidence.”, and the burden of proof is on those individuals who make these claims. It is up to them to produce high-quality evidence to support that what they claim is true, and, seriously, with a 100% success rate this should not prove too difficult, right? At this point you may argue that even if the effectiveness of hydroxychloroquine is less than 100%, but something like 80%, or 50% or 30%, that would still be significant and important. My answer to this is, yes, but this HAS to be established by well-designed clinical trials. At the moment, many clinical trials of hydroxychloroquine are ongoing, and several of these trials are sufficiently well-designed to yield unambiguous results. As I write this, among the best trials completed so far, one has indicated that hydroxychloroquine does not work as a prophylactic against COVID-19, and another has indicated that hydroxychloroquine does not reduce the risk of death among patients hospitalized with COVID-19. The FDA recently revoked its emergency use authorization of hydroxychloroquine, because based on the available evidence it’s unlikely to be effective in treating COVID-19 and any potential benefit from its use outweighs the potential risks. Many of these trials were designed to address the initial claims for hydroxychloroquine being very effective when administered alone or with certain antibiotics. A new claim has been made that hydroxychloroquine is only effective when it is administered with zinc, and new clinical trials are being performed to evaluate this possibility. As I stated above, I am skeptical about hydroxychloroquine, but I don’t want to be right, I want to save lives, and I hope the combination of hydroxychloroquine with zinc works. However, the public has to understand and accept the need to perform clinical trials and stop relying on testimonials and other anecdotal evidence. Image of a quack doctor selling remedies from his caravan; satirizing Gladstone's advocacy of the Home Rule Bill in Parliament is a Chromolithograph by T. Merry, 1889, and comes from the Welcome Collection. The image was modified and used here under an Attribution 4.0 International (CC BY 4.0) license, and no endorsement by the licensor is implied. There is a tsunami of misinformation being circulated about COVID-19, and many science communicators are trying to counter this with facts. I have already explained, for example, that COVID-19 is not like the flu, and the perils of ignoring this have already been exposed by the situation of Brazil whose president, Jair Bolsonaro, considers COVID-19 to be “a little flu”, and has done his best to undermine the efforts at mitigation by cities and states in his country. As a result of this, Brazil's COVID-19 cases have jumped to second place in the world after the United States. Another misinformation that is being circulated in social media is the notion that all the mitigation measures against COVID-19, from masks and social distancing to the stay at home orders, did not work to contain the spread of COVID-19. This can be demonstrated not to be true. There is abundant evidence that mitigation against COVID-19 reduced its spread both in the United States (for example: 1, 2, 3, 4, 5, 6, 7, and 8) and in other countries (1, 2, 3). There also is evidence from the past that these measures work. Even if you are not a scientist, it’s not difficult to figure out that a virus will spread more slowly in a population whose members interact less with each other compared to a population whose members interact more. This is really a no-brainer. Mitigation measures have prevented the health care system from being swamped with hospitalizations (what is known as “flattening the curve” of viral spread) as happened in populous localities that did not implement these measures soon enough. You have all read the stories and seen the pictures and videos of what uncontrolled spread of COVID-19 can do. I don’t need to belabor this point. But there are other important things that we have gained with mitigation that are not often mentioned.
There is a vast world-wide network of hundreds of thousands of scientists that has been working around the clock during the pandemic in hospitals, universities, companies, and other organizations investigating the virus, how it spreads, and meticulously analyzing the symptoms of the patients presenting with the disease. These scientists share findings, information, ideas, and experience, and test old and new treatments on cultured cells, animals, and humans. It is thanks to the action of these scientists that we now have a more accurate picture of the symptoms of COVID-19 and effective strategies to minimize the spread of the virus as we rescind stay-at-home orders and begin reopening our society. These scientists are also developing vaccines against COVID-19 and dealing with some unique problems in vaccine development pertinent to coronaviruses, and they are conducting studies to evaluate the benefit of other potential treatments for COVID-19. All in all, there are currently more than a thousand clinical trials all over the world investigating treatments for COVID-19. In these studies, some treatments that were initially touted as game changers such as hydroxychloroquine have so far not lived up to their initial promise. But other studies have shown more promise, such as that of the antiviral compound remdesivir, which is part of a remarkable story involving two decades of research into coronaviruses. One of the greatest achievements of scientists studying COVID-19 is a reevaluation of what the disease really is. The virus that causes COVID-19 is called “SARS-Cov-2”. This stands for “severe acute respiratory syndrome coronavirus 2”. This is because it was thought that the virus would predominantly infect the airways. But early in the pandemic, doctors in China treating COVID-19 patients made the observation that hospitalized patients were experiencing blood clots. Bloodwork analysis indicated that the patients with the most severe illness were strongly positive for some of the most common indicators of risk of increased clotting. Doctors in other countries also found the same thing. A study with almost 3,000 patients found that indeed, those patients administered anticoagulants survived longer: an effect that was even more striking in the sickest patients. The International Society on Thrombosis and Haemostasis issued a document where they provided an interim guidance to treat patients with COVID-19 based on their coagulation parameters. This and other evidence ranging from the molecular to the clinical, has contributed to shape an emerging theory regarding COVID-19 which proposes that, although the disease starts in the lungs, the virus then proceeds to attack the blood vessels. This theory would explain many of the observations made regarding the particular symptoms of COVID-19, and suggests many new lines of treatment. Apart from flattening the curve and other considerations, by delaying the spread of the virus through mitigation we have gained time and knowledge, and during a pandemic these two things are invaluable. Image from pixabay by Queven is used under a pixabay license. A group of skeptics who deny the severity of the coronavirus and the need for or effectiveness of the lockdown, recently piled up on me on Twitter bombarding me with dozens of tweets presenting their arguments with links and videos that “proved” their point. I decided that it was pertinent to write a blog post to deal with these issues. Recent results of preliminary antibody titers against the coronavirus in New York State have revealed that an estimated of 14.9% of the residents of the state (24.7% in New York City) have antibodies against the virus, which indicates they have been infected. The skeptics pounced on this and similar data from other places to argue that the true death rate from COVID19 is lower than had been calculated based on confirmed cases (which we knew already). So for example, if this number (14.9%) can be extrapolated to the total US population of 330 million people then 14.9% is 46.2 million people, then with 64,000 deaths so far from COVID19, the true death rate due to the virus is 0.13%. They claim this shows COVID19 is no worse than the flu for which the overall death rate is (as can be calculated from data from the CDC) about 0.13-14%. Thus, they argue, the lockdown was not justified, we harmed the economy for nothing, this whole thing has been a hoax perpetrated by the fake news media, and the so-called experts like Dr. Fauci have egg on their faces. Even if you are not a scientist, I hope you smell a rat in this argument. You have probably seen the social media posts of healthcare workers and residents from places like New York, Italy, and Spain stating that they had never seen something like this before. You may even know some of them. You have also seen the images. Morgues overflowing, bodies piling up, patients lying on the floors in corridors, shortages of personal protective equipment, and overworked health care workers coming down with the illness right and left. These people have dealt with the flu before, and this ain’t no flu. Indeed, in New York and in the U.S. as a whole, there was a spike in deaths compared to the past.
So what’s going on? First of all, the influenza cases presented in the CDC website are the influenza illnesses that show symptoms. This is important because as much as 50% of the influenza infections may be asymptomatic which indicates that the true number of infections, and therefore the true influenza death rates, are overestimated (I have made the mistake of quoting these inflated deaths rates for influenza too). You cannot use one figure derived from antibody titers in a calculation and compare it to another figure derived from symptomatic illnesses. Also, let’s not compare apples to oranges. The death rate in a region will depend on various local factors such as how early mitigation was begun, the population density of the region, how many people introduced the virus to the community, the quality and quantity of the health care, the overall health of the people, etc. Therefore it may be misleading to extrapolate the 14.9% total infection rate derived from antibody titers in samples from the State of New York to the whole country. According to the titer results, 2.9 million people are estimated to have been infected in New York State. If you take into account that New York State had 18,274 deaths, this is a death rate of 0.63 % for COVID19 in New York State. If you take the titer results of a 24.7% infection rate for New York City, which has a population of 8.4 million (2,074,800 infected), and has 12,287 confirmed deaths due to COVID19, that gives you a death rate of 0.59% (and using these death figures is an underestimation due to the time lag between infection and death, and the undercounting of COVID19 deaths). These figures are considerably higher than the flu’s overestimated rate of 0.13-0.14%, which is really closer to 0.04-0.05%. Although calculations from titers and numbers in other regions yield different death rates, all estimates are higher than the flu’s. Be it as it may, the antibody titer estimates are preliminary and there are several problems with the test kits used and the methodology employed to obtain the samples. We don’t know yet what the true number of infected people in the United States is, but we know this. So far we have had 64.000 deaths. If these deaths occurred as a result of even 10% or 20% of the people being infected (an unlikely high number for the country as a whole), that means that there are 90-80% of people who have not yet been infected. Thus there is substantial potential for more infection and more deaths, at least until herd immunity sets in. Depending on the local situation, the only thing protecting many people from COVID19 infections right now is mitigation and/or the lockdown. The only consistent thing about the preliminary antibody data so far is that it has not revealed very high titer estimates, which indicates that the mitigation/lockdown measures have been successful and were needed. And this makes sense, mitigation and lockdowns are working here and in other countries today and have been shown to have worked in the past too. There are also additional things to consider. COVID19 spreads faster than the flu and asymptomatic carriers can spread the disease for a longer time than the flu. Additionally, many people infected in the past with one strain of the flu have cross immunity to current strains of influenza and others have immunity due to the influenza vaccine. This limits the number of people that influenza can infect. On the other hand, COVID19 is a novel virus, and there is no immunity against it in our population. The number of people influenza can infect is limited, while the number of people that COVID19 can potentially infect is much higher (at least until herd immunity sets in). In a population without immunity, mitigation, or lockdown, this virus can spread like wildfire leading to steep increases in the number of infected, hospital admissions, and deaths depending on the quality of the health care system and the overall health of the population. Finally, the SARSCoV2 virus, which produces the COVID19 disease, is different from the flu virus, not only at the level of the virus, but also at the level of the disease. So, it’s not true that COVID19 is no worse than the flu, and it’s not true that social distancing and the lockdown were unnecessary. People who promote this misinformation and spread conspiracy theories are harming our society. However, the majority of people that do this are not evil. In fact, what they are doing is predictable, and we have a good idea why they are doing it. People are being laid off and facing the loss of their livelihood, and these people are genuinely concerned about their future due to circumstances they can’t control. They are angry and afraid for their loved ones and for themselves, and they fear the uncertainty of their economic situation more than they fear the virus. It is understandable that these people will fall for the simple “us vs them” arguments peddled by conspiracy mongers who are essentially selling them snake oil. But I have a message for these people. Spreading misinformation and lies, and protesting irresponsibly with no masks or social distancing is unnecessary. There is no need to smear the truth and be unsafe. The lockdown can’t go on forever, and everyone including those who had anything to do with putting it in place want to end it. We just need to do it in a responsible way that does not lead to a full-fledged second wave of the virus that overwhelms our health care system. Getting involved in the process and working with the system is better than attacking it. Call your representatives, learn about the local situation with respect to COVID19 and how it’s being dealt with, offer to get involved in the process, and contribute ideas to reopening while respecting and heeding the advice of health experts. This is the way to go. Conspiracy sign by Nick Youngson from Picpedia.Org used here with modifications under a Creative Commons 3 - CC BY-SA 3.0 license. Coronavirus image by Alissa Eckert, MS; Dan Higgins, MAM, from the CDC's Public Health Image Library is in the public domain. The drug hydroxychloroquine is being tested against COVID19, but there is still no compelling scientific evidence that it works, let alone that it is a “game changer” in our fight against COVID19. However, the president has claimed that there are very strong signs that it works on coronavirus, and the president’s economic adviser, Peter Navarro, has criticized the infectious disease expert, Dr. Anthony Fauci, for questioning alleged evidence hydroxychloroquine works on COVID19. The French researcher, Dr. Didier Raoult, who performed the original trial of hydroxychloroquine that generated all the current interest in the drug, now claims that he has treated 1,000 patients with COVID19 with a 99.3% success rate. In the news, I have read descriptions of patients that have recovered after being administered hydroxychloroquine in what has been called a “Lazarus effect” after the Biblical story where Jesus brought Lazarus back from the dead. So what is a scientist to make of this? I have acknowledged that science cannot operate in a vacuum. I recognize something that Dr. Fauci has also recognized, and that is that people need hope. However, as Dr. Fauci has also stated, scientists have the obligation to subject drugs to well-designed tests that will conclusively answer the question of whether a drug works or not. There seems to be a discrepancy between the quality of the evidence that scientists and non-scientist will accept to declare that a drug works, and there is the need to resolve this discrepancy. People anxiously waiting for evidence regarding whether hydroxychloroquine works, will understandably concentrate on patients that recover. Therefore they are more prone to make positive information the focus of their attention. Any remarkable cases where people recover (Lazarus effects) will invariably be pushed to the forefront of the news, and presented as evidence that the drug works wonders. What people need to understand, is that these “Lazarus” cases always occur, even in the absence of effective interventions. We all react to disease and drugs differently. Someone somewhere will always recover sooner and better than others. How do we know whether one of these Lazarus cases was a real effect of the drug or a happenstance? Isolated cases of patients who get better, no matter how spectacular, are meaningless. Scientists look at people who recover from an illness after being given a drug in the context of the whole population of patients treated with the drug to derive a proportion. The goal is then to compare this proportion to that of a population of patients not given the drug. Scientists also have to consider both positive and negative information. For the purposes of determining whether a drug works, patients that don’t recover are just as important to take into account as those that do. What if a drug benefits some patients to a great extent but kills others? Depending on the condition being treated, it may not be justified to use this drug until you can identify the characteristics of the patients that will be benefited by the drug. To do all the above properly, you need to carry out a clinical trial. No matter how desperate people are, and no matter how angry it makes them to hear otherwise, this is the only way to establish whether a drug works or not. Once we accept the need for a clinical trial to establish whether a drug works, another issue is trial design. A trial carried out by scientists is not valid just because it happened. There are optimally-designed trials and suboptimal or poorly designed trials. There are several things a optimally designed trial must have. 1) The problem with much of the evidence regarding hydroxychloroquine is that it has been tested against COVID-19 in very small trials, and clinical trials of small size are notorious for giving inaccurate results. You need a large enough sample size to make sure your results are valid. 2) Another problem is: what you are comparing the drug against? Normally, you give the drug to a group of patients, and you compare the results to another group that simultaneously received an inert dummy pill (a placebo), or at least to a group of patients that received the best available care. This is what is called a control group. In many hydroxychloroquine trials there were no formal control groups, but rather the results were loosely compared to “historical controls”, in other words, to how well a group of patients given no drug fared in the past. But this procedure can be very inaccurate as there is considerable variation in such controls. 3) Another issue is the so called placebo effect. The psychology of patients knowing that they are being given a new potentially lifesaving drug is different from that of patients that are being treated with regular care. Just because of this, the patients being given the drug may experience an improvement (the so called placebo effect). To avoid this bias, the patients and even the attending physicians and nurses are often blinded as to the nature of the treatment in the best trials. Most hydroxychloroquine studies were not performed blind. 4) Even if you are comparing two groups, drug against placebo or best care, you need to allocate the patients to both groups in a random fashion to make sure that you do not end up with a mix of patients in a group that has some characteristic that is overrepresented compared to the other group, as this could influence the results of the trial. Most hydroxychloroquine studies were not randomized. These are but a few factors to consider when performing a trial to determine whether a drug works. These and other factors, if they are not carefully dealt with, can result in a trial yielding biased results that may over or underestimate the effectiveness of a drug. Due to budget constraints, urgency, or other reasons, scientists sometimes carry out very preliminary trials that are not optimal just to give a drug an initial “look see” or to gain experience with the administration of the drug in a clinical setting. But these trials are just that, preliminary, and there is no scientific justification to base any decision regarding the promotion of a drug based on this type of trials. The FDA recently has urged caution against the use of hydroxychloroquine outside the hospital setting due to reports of serious heart rhythm problems in patients with COVID-19 treated with the drug. A recent study with US Veterans who were treated with hydroxychloroquine found a higher death rate among patients who were administered the drug (to be fair, this study was retrospective and therefore did not randomize the allocation of patients to treatments, so this could have biased the results). Even though I am skeptical about this drug, I would rather save lives than be right. I really hope it works, but the general public needs to understand that neither reported Lazarus effects nor suboptimal clinical trials will give us the truth. The 1310-11painting The Raising of Lazarus by Duccio di Buoninsegna is in the public domain. The image of hydroxychloroquine by Fvasconcellos is in the public domain. |
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