The Only Hydroxychloroquine Story You Need to Read
Dr. Adalja is focused on emerging infectious disease, pandemic preparedness, and biosecurity. He has served on US government panels tasked with developing guidelines for the treatment of plague, botulism, and anthrax in mass casualty settings and the system of care for infectious disease emergencies, and as an external advisor to the New York City Health and Hospital Emergency Management Highly Infectious Disease training program, as well as on a FEMA working group on nuclear disaster recovery. Dr. Adalja is an Associate Editor of the journal Health Security. He was a coeditor of the volume Global Catastrophic Biological Risks, a contributing author for the Handbook of Bioterrorism and Disaster Medicine, the Emergency Medicine CorePendium, Clinical Microbiology Made Ridiculously Simple, UpToDate's section on biological terrorism, and a NATO volume on bioterrorism. He has also published in such journals as the New England Journal of Medicine, the Journal of Infectious Diseases, Clinical Infectious Diseases, Emerging Infectious Diseases, and the Annals of Emergency Medicine. He is a board-certified physician in internal medicine, emergency medicine, infectious diseases, and critical care medicine. Follow him on Twitter: @AmeshAA
In the early days of a pandemic caused by a virus with no existing treatments, many different compounds are often considered and tried in an attempt to help patients.
It all relates back to a profound question: How do we know what we know?
Many of these treatments fall by the wayside as evidence accumulates regarding actual efficacy. At that point, other treatments become standard of care once their benefit is proven in rigorously designed trials.
However, about seven months into the pandemic, we're still seeing political resurrection of a treatment that has been systematically studied and demonstrated in well-designed randomized controlled trials to not have benefit.
The hydroxychloroquine (and by extension chloroquine) story is a complicated one that was difficult to follow even before it became infused with politics. It is a simple fact that these drugs, long approved by the Food and Drug Administration (FDA), work in Petri dishes against various viruses including coronaviruses. This set of facts provided biological plausibility to support formally studying their use in the clinical treatment and prevention of COVID-19. As evidence from these studies accumulates, it is a cognitive requirement to integrate that knowledge and not to evade it. This also means evaluating the rigor of the studies.
In recent days we have seen groups yet again promoting the use of hydroxychloroquine in, what is to me, a baffling disregard of the multiple recent studies that have shown no benefit. Indeed, though FDA-approved for other indications like autoimmune conditions and preventing malaria, the emergency use authorization for COVID-19 has been rescinded (which means the government cannot stockpile it). Still, however, many patients continue to ask for the drug, compelled by political commentary, viral videos, and anecdotal data. Yet most doctors (like myself) are refusing to write the prescriptions outside of a clinical trial – a position endorsed by professional medical organizations such as the American College of Physicians and the Infectious Diseases Society of America. Why this disconnect?
It all relates back to a profound question: How do we know what we know? In science, we use the scientific method – the process of observing reality, coming up with a hypothesis about what might be true, and testing that hypothesis as thoroughly as possible until we discover the objective truth.
The confusion we're seeing now stems from an inability to distinguish between anecdotes reported by physicians (observational data) and an actual evidence base. This is understandable among the general public but when done by a healthcare professional, it reveals a disdain for reason, logic, and the scientific method.
The Difference Between Observational Data and Randomized Controlled Trials
The power of informal observation is crucial. It is part of the scientific method but primarily as a basis for generating hypotheses that we can test. How do we conduct medical tests? The gold standard is the double-blind, randomized, placebo-controlled trial. This means that neither the researchers nor the volunteers know who is getting a drug and who is getting a sugar pill. Then both groups of the trial, called arms, can be compared to determine whether the people who got the drug fared better. This study design prevents biases and the placebo effect from confounding the data and undermining the veracity of the results.
For example, a seemingly beneficial effect might be seen in an observational study with no blinding and no control group. In such a case, all patients are openly given the drug and their doctors observe how they do. A prime example is the 36-patient single-arm study from France that generated a tremendous amount of interest after President Trump tweeted about it. But this kind of a study by its nature cannot answer the critical question: Was the positive effect because of hydroxychloroquine or just the natural course of the illness? In other words, would someone have recovered in a similar fashion regardless of the drug? What is the role of the placebo effect?
These are reasons why it is crucial to give a placebo to a control group that is as similar in every respect as possible to those receiving the intervention. Then we attempt to find out by comparing the two groups: What is the side effect profile of the drug? Are the groups large enough to detect a relatively rare safety concern? How long were the patients followed for? Was something else responsible for making the patients get better, such as the use of steroids (as likely was the case in the Henry Ford study)?
Looking at the two major hydroxychloroquine trials, it is apparent that, when studied using the best tools of clinical trials, no benefit is likely to occur.
All of these considerations amount to just a fraction of the questions that can be answered more definitively in a well-designed large randomized controlled trial than in observational studies. Indeed, an observational study from New York failed to show any benefit in hospitalized patients, showing how unclear and disparate the results can be with these types of studies. A New York retrospective study (which examined patient outcomes after they were already treated) had similar results and included the use of azithromycin.
When evaluating a study, it is also important to note whether conflicts of interest exist, as well as the quality of the peer review and the data itself. In the case of the French study, for example, the paper was published in a journal in which one of the authors was editor-in-chief, and it was accepted for publication after 24 hours. Patients who fared poorly on hydroxychloroquine were also left out of the study altogether, skewing the results.
What Randomized Controlled Trials Have Shown
Looking at the two major hydroxychloroquine trials, it is apparent that, when studied using the best tools of clinical trials, no benefit is likely to occur. The most important of these studies to announce results was part of the Recovery trial, which was designed to test multiple interventions in the treatment of COVID-19. This trial, which has yet to be formally published, was a randomized controlled trial that involved over 1500 hospitalized patients being administered hydroxychloroquine compared to over 3000 who did not receive the medication. Clinical testing requires large numbers of patients to have the power to demonstrate statistical significance -- the threshold at which any apparent benefit is more than you would expect by random chance alone.
In this study, hydroxychloroquine provided no mortality benefit or even a benefit in hospital length of stay. In fact, the opposite occurred. Hydroxychloroquine patients were more likely to stay in the hospital longer and were more likely to require mechanical ventilation. Additionally, smaller randomized trials conducted in China have not shown benefit either.
Another major study involved the use of hydroxychloroquine to prevent illness in people who were exposed to COVID-19. These results, published in The New England Journal of Medicine, included over 800 patients who were studied in a randomized double-blind controlled trial and also failed to show any benefit.
But what about adding the antibiotic azithromycin in conjunction with hydroxychloroquine? A three-arm randomized controlled study involving over 500 patients hospitalized with mild to moderate COVID-19 was conducted. Its results, also published in The New England Journal of Medicine, failed to show any benefit – with or without azithromycin – and demonstrated evidence of harm. Those who received these treatments had elevations of their liver function tests and heart rhythm abnormalities. These findings hold despite the retraction of an observational study showing similar results.
Additionally, when used in combination with remdesivir – an experimental antiviral – hydroxychloroquine has been shown to be associated with worse outcomes and more side effects.
But what about in mildly ill patients not requiring hospitalization? There was no benefit found in a randomized double-blind placebo-controlled trial of 400 patients, the majority of whom were given the drug within one day of symptoms.
Some randomized controlled studies have yet to report their findings on hydroxychloroquine in non-hospitalized patients, with the use of zinc (which has some evidence in the treatment of the common cold, another ailment that can be caused by coronaviruses). And studies have yet to come out regarding whether hydroxychloroquine can prevent people from getting sick before they are even exposed. But the preponderance of the evidence from studies designed specifically to find benefit for treating COVID-19 does not support its use outside of a research setting.
Today – even with some studies (including those with zinc) still ongoing – if a patient asked me to prescribe them hydroxychloroquine for any severity or stage of illness, with or without zinc, with or without azithromycin, I would refrain. I would explain that, based on the evidence from clinical trials that has been amassed, there is no reason to believe that it will alter the course of illness for the better.
Failing to recognize the reality of the situation runs the risk of crowding out other more promising treatments and creating animosity where none should exist.
What has been occurring is a continual shifting of goalposts with each negative hydroxychloroquine study. Those in favor of the drug protest that a trial did not include azithromycin or zinc or wasn't given at the right time to the right patients. While there may be biological plausibility to treating illness early or combining treatments with zinc, it can only be definitively shown in a randomized, controlled prospective study.
The bottom line: A study that only looks at past outcomes in one group of patients – even when well conducted – is at most hypothesis generating and cannot be used as the sole basis for a new treatment paradigm.
Some may argue that there is no time to wait for definitive studies, but no treatment is benign. The risk/benefit ratio is not the same for every possible use of the drug. For example, hydroxychloroquine has a long record of use in rheumatoid arthritis and systemic lupus (whose patients are facing shortages because of COVID-19 related demand). But the risk of side effects for many of these patients is worth taking because of the substantial benefit the drug provides in treating those conditions.
In COVID-19, however, the disease apparently causes cardiac abnormalities in a great deal of many mild cases, a situation that should prompt caution when using any drugs that have known effects on the cardiac system -- drugs like hydroxychloroquine and azithromycin.
My Own Experience
It is not the case that every physician was biased against this drug from the start. Indeed, most of us wanted it to be shown to be beneficial, as it was a generic drug that was widely available and very familiar. In fact, early in the pandemic I prescribed it to hospitalized patients on two occasions per a hospital protocol. However, it is impossible for me as a sole clinician to know whether it worked, was neutral, or was harmful. In recent days, however, I have found the hydroxychloroquine talk to have polluted the atmosphere. One recent patient was initially refusing remdesivir, a drug proven in large randomized trials to have effectiveness, because he had confused it with hydroxychloroquine.
Moving On to Other COVID Treatments: What a Treatment Should Do
The story of hydroxychloroquine illustrates a fruitless search for what we are actually looking for in a COVID-19 treatment. In short, we are looking for a medication that can decrease symptoms, decrease complications, hasten recovery, decrease hospitalizations, decrease contagiousness, decrease deaths, and prevent infection. While it is unlikely to find a single antiviral that can accomplish all of these, fulfilling even just one is important.
For example, remdesivir hastens recovery and dexamethasone decreases mortality. Definitive results of the use of convalescent plasma and immunomodulating drugs such as siltuxamab, baricitinib, and anakinra (for use in the cytokine storms characteristic of severe disease) are still pending, as are the trials with monoclonal antibodies.
While it was crucial that the medical and scientific community definitively answer the questions surrounding the use of chloroquine and hydroxychloroquine in the treatment of COVID-19, it is time to face the facts and accept that its use for the treatment of this disease is not likely to be beneficial. Failing to recognize the reality of the situation runs the risk of crowding out other more promising treatments and creating animosity where none should exist.
Dr. Adalja is focused on emerging infectious disease, pandemic preparedness, and biosecurity. He has served on US government panels tasked with developing guidelines for the treatment of plague, botulism, and anthrax in mass casualty settings and the system of care for infectious disease emergencies, and as an external advisor to the New York City Health and Hospital Emergency Management Highly Infectious Disease training program, as well as on a FEMA working group on nuclear disaster recovery. Dr. Adalja is an Associate Editor of the journal Health Security. He was a coeditor of the volume Global Catastrophic Biological Risks, a contributing author for the Handbook of Bioterrorism and Disaster Medicine, the Emergency Medicine CorePendium, Clinical Microbiology Made Ridiculously Simple, UpToDate's section on biological terrorism, and a NATO volume on bioterrorism. He has also published in such journals as the New England Journal of Medicine, the Journal of Infectious Diseases, Clinical Infectious Diseases, Emerging Infectious Diseases, and the Annals of Emergency Medicine. He is a board-certified physician in internal medicine, emergency medicine, infectious diseases, and critical care medicine. Follow him on Twitter: @AmeshAA
This man spent over 70 years in an iron lung. What he was able to accomplish is amazing.
It’s a sight we don’t normally see these days: A man lying prone in a big, metal tube with his head sticking out of one end. But it wasn’t so long ago that this sight was unfortunately much more common.
In the first half of the 20th century, tens of thousands of people each year were infected by polio—a highly contagious virus that attacks nerves in the spinal cord and brainstem. Many people survived polio, but a small percentage of people who did were left permanently paralyzed from the virus, requiring support to help them breathe. This support, known as an “iron lung,” manually pulled oxygen in and out of a person’s lungs by changing the pressure inside the machine.
Paul Alexander was one of several thousand who were infected and paralyzed by polio in 1952. That year, a polio epidemic swept the United States, forcing businesses to close and polio wards in hospitals all over the country to fill up with sick children. When Paul caught polio in the summer of 1952, doctors urged his parents to let him rest and recover at home, since the hospital in his home suburb of Dallas, Texas was already overrun with polio patients.
Paul rested in bed for a few days with aching limbs and a fever. But his condition quickly got worse. Within a week, Paul could no longer speak or swallow, and his parents rushed him to the local hospital where the doctors performed an emergency procedure to help him breathe. Paul woke from the surgery three days later, and found himself unable to move and lying inside an iron lung in the polio ward, surrounded by rows of other paralyzed children.
Hospitals were commonly filled with polio patients who had been paralyzed by the virus before a vaccine became widely available in 1955. Associated Press
Paul struggled inside the polio ward for the next 18 months, bored and restless and needing to hold his breath when the nurses opened the iron lung to help him bathe. The doctors on the ward frequently told his parents that Paul was going to die.But against all odds, Paul lived. And with help from a physical therapist, Paul was able to thrive—sometimes for small periods outside the iron lung.
The way Paul did this was to practice glossopharyngeal breathing (or as Paul called it, “frog breathing”), where he would trap air in his mouth and force it down his throat and into his lungs by flattening his tongue. This breathing technique, taught to him by his physical therapist, would allow Paul to leave the iron lung for increasing periods of time.
With help from his iron lung (and for small periods of time without it), Paul managed to live a full, happy, and sometimes record-breaking life. At 21, Paul became the first person in Dallas, Texas to graduate high school without attending class in person, owing his success to memorization rather than taking notes. After high school, Paul received a scholarship to Southern Methodist University and pursued his dream of becoming a trial lawyer and successfully represented clients in court.
Paul Alexander, pictured here in his early 20s, mastered a type of breathing technique that allowed him to spend short amounts of time outside his iron lung. Paul Alexander
Paul practiced law in North Texas for more than 30 years, using a modified wheelchair that held his body upright. During his career, Paul even represented members of the biker gang Hells Angels—and became so close with them he was named an honorary member.Throughout his long life, Paul was also able to fly on a plane, visit the beach, adopt a dog, fall in love, and write a memoir using a plastic stick to tap out a draft on a keyboard. In recent years, Paul joined TikTok and became a viral sensation with more than 330,000 followers. In one of his first videos, Paul advocated for vaccination and warned against another polio epidemic.
Paul was reportedly hospitalized with COVID-19 at the end of February and died on March 11th, 2024. He currently holds the Guiness World Record for longest survival inside an iron lung—71 years.
Polio thankfully no longer circulates in the United States, or in most of the world, thanks to vaccines. But Paul continues to serve as a reminder of the importance of vaccination—and the power of the human spirit.
““I’ve got some big dreams. I’m not going to accept from anybody their limitations,” he said in a 2022 interview with CNN. “My life is incredible.”
When doctors couldn’t stop her daughter’s seizures, this mom earned a PhD and found a treatment herself.
Twenty-eight years ago, Tracy Dixon-Salazaar woke to the sound of her daughter, two-year-old Savannah, in the midst of a medical emergency.
“I entered [Savannah’s room] to see her tiny little body jerking about violently in her bed,” Tracy said in an interview. “I thought she was choking.” When she and her husband frantically called 911, the paramedic told them it was likely that Savannah had had a seizure—a term neither Tracy nor her husband had ever heard before.
Over the next several years, Savannah’s seizures continued and worsened. By age five Savannah was having seizures dozens of times each day, and her parents noticed significant developmental delays. Savannah was unable to use the restroom and functioned more like a toddler than a five-year-old.
Doctors were mystified: Tracy and her husband had no family history of seizures, and there was no event—such as an injury or infection—that could have caused them. Doctors were also confused as to why Savannah’s seizures were happening so frequently despite trying different seizure medications.
Doctors eventually diagnosed Savannah with Lennox-Gaustaut Syndrome, or LGS, an epilepsy disorder with no cure and a poor prognosis. People with LGS are often resistant to several kinds of anti-seizure medications, and often suffer from developmental delays and behavioral problems. People with LGS also have a higher chance of injury as well as a higher chance of sudden unexpected death (SUDEP) due to the frequent seizures. In about 70 percent of cases, LGS has an identifiable cause such as a brain injury or genetic syndrome. In about 30 percent of cases, however, the cause is unknown.
Watching her daughter struggle through repeated seizures was devastating to Tracy and the rest of the family.
“This disease, it comes into your life. It’s uninvited. It’s unannounced and it takes over every aspect of your daily life,” said Tracy in an interview with Today.com. “Plus it’s attacking the thing that is most precious to you—your kid.”
Desperate to find some answers, Tracy began combing the medical literature for information about epilepsy and LGS. She enrolled in college courses to better understand the papers she was reading.
“Ironically, I thought I needed to go to college to take English classes to understand these papers—but soon learned it wasn’t English classes I needed, It was science,” Tracy said. When she took her first college science course, Tracy says, she “fell in love with the subject.”
Tracy was now a caregiver to Savannah, who continued to have hundreds of seizures a month, as well as a full-time student, studying late into the night and while her kids were at school, using classwork as “an outlet for the pain.”
“I couldn’t help my daughter,” Tracy said. “Studying was something I could do.”
Twelve years later, Tracy had earned a PhD in neurobiology.
After her post-doctoral training, Tracy started working at a lab that explored the genetics of epilepsy. Savannah’s doctors hadn’t found a genetic cause for her seizures, so Tracy decided to sequence her genome again to check for other abnormalities—and what she found was life-changing.
Tracy discovered that Savannah had a calcium channel mutation, meaning that too much calcium was passing through Savannah’s neural pathways, leading to seizures. The information made sense to Tracy: Anti-seizure medications often leech calcium from a person’s bones. When doctors had prescribed Savannah calcium supplements in the past to counteract these effects, her seizures had gotten worse every time she took the medication. Tracy took her discovery to Savannah’s doctor, who agreed to prescribe her a calcium blocker.
The change in Savannah was almost immediate.
Within two weeks, Savannah’s seizures had decreased by 95 percent. Once on a daily seven-drug regimen, she was soon weaned to just four, and then three. Amazingly, Tracy started to notice changes in Savannah’s personality and development, too.
“She just exploded in her personality and her talking and her walking and her potty training and oh my gosh she is just so sassy,” Tracy said in an interview.
Since starting the calcium blocker eleven years ago, Savannah has continued to make enormous strides. Though still unable to read or write, Savannah enjoys puzzles and social media. She’s “obsessed” with boys, says Tracy. And while Tracy suspects she’ll never be able to live independently, she and her daughter can now share more “normal” moments—something she never anticipated at the start of Savannah’s journey with LGS. While preparing for an event, Savannah helped Tracy get ready.
“We picked out a dress and it was the first time in our lives that we did something normal as a mother and a daughter,” she said. “It was pretty cool.”