A few people have recently mentioned that I haven’t published a Cloudy Media Blog article in a while. I love the enthusiasm for these blogs and I really want to provide you, my faithful readers, with evidence-based information, especially during such tenious times. But I have to admit something. I am sick of it.
Don’t get me wrong, I love writing. And researching a new story is always refreshing and exciting. I’m not even sick of COVID (pun intended) to the extent that the SARS-CoV-2 virus is fascinating to me. What I am sick of is people. I suppose this is ironic because I actually haven’t seen that many people in real life in the past six months, but I “see” them online every day.
News reports of large gatherings like the Chainsmokers concert in the Hamptons and the sleep-away camp in Georgia frustrate me to my core. Add to that the neverending series of “experts” who go online spouting misinformation that goes viral and stirs up confusion, and I feel helpless to stop it. Sometimes I try, but if the past couple weeks have taught me anything it’s that facts and scientific data do little to dissuade someone who vehemently believes that everyone (including me) has an agenda. Sure, biases do exist and even unconscious ones play a role in the choice of each word as I type this, but I am a scientist and I deal with data.
Data has no agenda, political or otherwise, yet some people don’t trust it.
Honestly, I don’t know how to live in a world where nothing you see, hear, or read is trustworthy. Obviously I’m not saying that everything is truthful. Anyone can go online and say whatever they want–I’m doing it right now. Having a high index of suspicion is a good thing. What I truly do not understand is when the experts are the targets of doubt or when the actual scientific data are ignored and misrepresented. So today I’m going to take a little time to explain the scientific method, discuss how studies are conducted and published, and how in all of its flaws and weaknesses, the scientific method is the arbiter of truth.
First and foremost, it is important to recognize that science itself is not data or information. Science is a method of acquiring knowledge. It involves formulating a hypothesis and designing experiments to test that hypothesis. When I was growing up, I never really thought that I was creative because I wasn’t artistic or musically-inclined. It wasn’t until I was a grad student designing experiments to figure out how a molecule made abundantly during viral infections affected white blood cells that I understood how creative I really was.
There was no one single or simple way to test my hypothesis that this molecule, called interferon, did more than interfere with viral replication. I hypothesized that it also affected T cells that weren’t responding to the virus (we called them “bystander” T cells because they were sort of just hanging around during the infection). So I tested this hypothesis in all the ways my advisor, lab-mates, and I could come up with, which was a lot of different experiments. Five years worth of experiments, if I’m being truthful, with modifications based on what we learned, suggestions by other scientists, and replication, replication, replication. A successful scientist is creative, lucky, and most of all persistent.
When we thought we had a rational explanation for interferon’s affects on bystander T cells, our job was not over. The next step was the arduous process of publishing the study in a journal. These days it seems as if medical studies go straight to the mainstream press, but it’s important to understand that they too undergo the this process of publication in a medical journal. And to be perfectly clear, every news article reporting on a scientific study should include a link to the study so their interpretation of the data can be vetted by readers.
To publish the study in a journal, we had to write up the story in the correct format (each journal is different), create all the figures, ensure that the analysis and statistics were done correctly, submit it to the journal, and cross our fingers that it would go out for peer review. Every journal has a board of editors that look at each study and determine if it’s worthy of consideration. If it is, two-four other scientists are sent the manuscript to evaluate. These scientists serve as peer reviewers and are anonymous to the study investigators. The peer reviewers provide feedback and often decide if the paper is accepted or rejected. Sometimes, if the study authors are lucky, a few rounds of revisions (with or without additional experiments) will get the study accepted. This process typically takes months if not years from when the study was originally submitted.
Today there are pre-print servers where study investigators can upload their paper before it is accepted into a journal. It’s important to take these studies with a grain of salt because they have not yet be officially peer-reviewed, though I would consider all the world’s eyes on them and discussion on social media at least some form of peer review. The pandemic hasn’t otherwise changed the process of peer review and publication, though the importance of studies on COVID-19 has certainly expedited the turnaround time from submission to decision.
When a study is published in a scientific journal, the data are then available for other scientists to evaluate in the context of their own work and knowledge. What this means is that the conclusions are not gospel, it is up to the scientific community to appraise the methodology and the findings, to replicate them in their own systems, and to challenge the data (not outright disagree with no discourse, but to contextually appraise the findings). When you see scientists and medical professionals disagree, it’s not distrust (mostly), it is nuanced discourse based on the evidence we have so far.
The scientific method ultimately leads us to truth. By conducting experiments and publishing data, other scientists can take one body of work and expand upon it. Each layer provides more clarity as to how biological processes work, but it cannot happen overnight. In this way, science is iterative and self-correcting. However, along the way it can appear quite messy. This is how it has always been, but the world’s attention is usually focused somewhere else. It is tough to work under a magnifying glass, making each little flaw appear 100x bigger. Many new findings discovered during this pandemic have prompted clinical change, which has at times made it appear as if the experts are waffling. When recommendations change (worse when they appear to flip-flop), people can take that to mean that no one knows what they’re talking about. In reality, this is how we make progress in medicine. We have to be patient with the scientific method, especially today. It astounds me how much we’ve learned about a brand new virus in just eight months and it’s just the tip of the iceberg.
For an example of how the scientific method leads us to truth, let’s take a look at the studies that have evaluated the drug hydroxychloroquine (HCQ). Early in the pandemic, clinicians were desperate to try anything to save patients dying from COVID-19. HCQ had been shown to inhibit coronavirus replication (specifically SARS-CoV-1 or SARS “classic”) in Petri dishes in a lab. This study was published in 2005 and has been spread around social media lately suggesting that Dr. Anthony Fauci was somehow lying about it. Notably, he was not actually associated with this study in any way. Regardless, because of these in vitro experiments, it’s not surprising that HCQ was at the top of the list of potential therapies at the beginning of the pandemic. But in vitro effects don’t always translate to clinical success. In vitro studies are found at the bottom of the evidence hierarchy (see figure above), meaning that these studies provide little to inform clinical decision making. HCQ needed to be tested in patients with COVID-19.
The first studies to be peer reviewed and published showed that HCQ might have an affect in people with COVID-19, prompting a sliver of hope and unfortunate politicization. Notably, these early studies were observational case series and cohort studies, which are are further up the evidence hierarchy than the in vitro studies. However, they are not as rigorous as randomized controlled trials because a variety of matters can confound the results. Some issues with these observational studies include lack of control groups, no blinding, and baseline differences among groups, to name a few. Importantly, these observational studies cannot prove a drug is effective, that is, whether it is better than placebo. For that, randomized trials are needed.
It takes more time to set up randomized trials so they were slower to publication, but as of today there have been a handful (see a complete list at the end of this article). No randomized trial has shown that HCQ reduces mortality in patients with COVID-19. Likewise, HCQ also does not prevent COVID-19 when given after an exposure. Importantly, COVID-19 causes some very severe cardiovascular complications and HCQ has been shown to exacerbate these dangerous complications, which raises the bar for establishing efficacy. What I mean by this is that the benefits of the drug must outweigh the potential harms or it will never be approved for use. As each randomized trial was published, its methods and results were evaluated and incorporated into the existing knowledge base. When each additional randomized trial shows similar results, the findings are more and more likely to be true.
Systematic reviews are even further up the evidence hierarchy because they synthesize all the studies together. They will often align with the results of the randomized trials when those studies agree. So far, two systematic reviews have been published and neither demonstrated that HCQ reduces mortality in patients with COVID-19.
It’s important to point out that mortality is not the only outcome evaluated in these randomized trials and systematic reviews. In a few trials, HCQ was shown to reduce the duration of illness. WHAAAT, it does work?!?–you may be asking, but let me ask you this: Would you take a drug that reduced the number of days you were feeling ill if it also increased the likelihood that you would have longterm cardiac problems? We know that COVID-19 already does a number on the heart, so anything that could contribute to making that worse is simply not worth the risk. The benefits of HCQ simply do not outweigh the risks.
I have thought about this acutely because hypothetically if HCQ worked and I got COVID-19, I couldn’t be treated with it. I have what’s known as long QT syndrome. The heart is a pump with two essential phases: contraction and relaxation. My heart takes longer to relax from each beat (what’s known medically as having a prolonged QT interval on an EKG). So if my heart rate is too high, it can start to contract before it’s fully relaxed from the previous beat and cause an arrhythmia. There are a variety of medications that I cannot take because they contribute to further prolonging the QT interval, among them is HCQ.
A question that is often posed at this juncture is why HCQ is approved for other conditions, specifically malaria and some autoimmune disorders such as lupus. The answer is actually quite straightforward – HCQ does more to benefit these patients than harm them. Notably, most of these conditions do not have cardiac complications like COVID-19. We often fall into these false dichotomies that something (a drug, vaccine, or anything really) is either good or bad. This is a trap. HCQ is good for treating lupus (the benefits outweigh the risks), but bad for treating COVID-19 (the risks outweigh the benefits).
Finally, the very top of the evidence hierarchy are clinical practice guidelines. These are derived by specialists who evaluate all of the evidence and provide actionable recommendations for healthcare professionals. Like the research they evaluate, recommendations are fluid and reflect current understanding. The Infectious Disease Society of America recently updated their recommendations for HCQ. Previously, they recommended HCQ only in the context of a clinical trial, but because it is now clear that the risks of cardiac complications outweigh the benefits of reducing illness by a few days, they no longer recommend HCQ for any patients hospitalized with COVID-19.
I think it’s important to take a moment to stop here and point out that not all hypotheses about HCQ and COVID-19 are solved. It is clear that HCQ is no miracle cure, but that doesn’t mean that a certain patient population won’t respond better or some combination of HCQ and other agents won’t work. There are currently 250 clinical trials registered on clinicaltrials.gov to test HCQ in patients with COVID-19, many designed to test these various hypotheses. However, they have to be conducted safely and notably in patients at low risk for cardiac complications.
To be a scientist is to be open minded and to integrate and layer new information into the existing knowledge base. This is not something that is easily understood by people outside the scientific community. Scientists undergo years of training to obtain a doctorate in philosophy–literally learning how to think. This is often followed by more training to hone this thought process and establish expertise before becoming an independent investigator or going off in one of various other career paths–the one I chose satisfyingly continues to involve all that creativity I didn’t think I had.
It’s disheartening when all that experience is tossed aside because one rogue physician gets in front of a camera or because HCQ has turned into a political chess piece. I don’t appreciate the media tactics of either side of the spectrum, but I didn’t get the information for this blog from Facebook, Youtube, a news article, or left or right networks. This is what the primary data shows, this is how clinical research works, and this is how we get to the truth.
Published randomized trials on HCQ in patients with COVID-19
- Hydroxychloroquine in Nonhospitalized Adults With Early COVID-19: A Randomized Trial
- Hydroxychloroquine for Early Treatment of Adults with Mild Covid-19: A Randomized-Controlled Trial
- Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial
- Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19
- Effect of High vs Low Doses of Chloroquine Diphosphate as Adjunctive Therapy for Patients Hospitalized With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection: A Randomized Clinical Trial
- A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19
Published systematic reviews on HCQ in patients with COVID-19
- A Rapid Systematic Review of Clinical Trials Utilizing Chloroquine and Hydroxychloroquine as a Treatment for COVID-19
- Drug Treatments for COVID-19: Living Systematic Review and Network Meta-analysis
Preprint randomized trials on HCQ in patients with COVID-19 (take with grain of salt)