Angie Wan, BA1 and Amy Zhang, BA2
1 Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
2 University of Chicago, Chicago, IL 60637, USA
“It will be wonderful. It will be so beautiful. It will be a gift from heaven, if it works,” said President Trump of hydroxychloroquine, an antimalarial drug that has mixed initial data supporting its usage with COVID-19 [1-2]. Despite the limited evidence, President Trump has heralded hydroxychloroquine as a miracle drug, asking, “What really do we have to lose?”
The siren draw of miracle cures and magic bullets has long been a fixture of medicine and public attention. Never was this more so than in the late-nineteenth and early-twentieth-centuries where advancements in medicine made Thomas Huxley’s vision of a “cunningly-contrived torpedo,” able to hone in on and destroy particular pathogens without harming the human host, seem more within the realm of reality rather than the science fiction of his grandson Aldous Huxley’s works [3].
Among the physician scientists of the time working on such targeted medicines for the treatment of infectious disease was Dr. Paul Ehrlich. Inspired by his research in immunology and the properties of certain dyes that could selectively stain cells, he coined the term, Zauberkugel, or “magic bullet,” and applied it to his new miracle drug, Salvarsan.
Discovered in 1909 by Ehrlich and Sahachiro Hata, Salvarsan, a derivative of arsenic, was the first effective treatment for syphilis, at the time a devastating disease. Left untreated, syphilis can cause significant disfiguration, aortic aneurysms, and perhaps most feared of all, a paralytic dementia. In some estimates, complications of tertiary syphilis accounted for around 10-30% of mental hospital admissions across Europe and the United States at the time [4].
Yet Salvarsan, while being a vast improvement on older mercury treatments, was as historian Allan Brandt put it, “no magic bullet” [5]. Salvarsan had a litany of potential side effects ranging from limb loss to multisystem failure and shock. Some of these side effects were the result of its difficult administration. Chief curator of Case Western Reserve University’s Dittrick Museum of Medical History Dr. Amanda Mahoney notes that in the nineteenth century, intravenous access often required venous cutdown by a surgeon, which carried its own risk of complication including cellulitis, hematoma, phlebitis, venous thrombosis, and venous/nerve/arterial transection. Additionally, even with perfect administration, Salvarsan could only prevent transmission and progression to later stages of syphilis. It was less useful if the patient had already reached the later terminal stages of the disease.
Salvarsan was not the only “magic bullet” discovered by Ehrlich, who also applied the term to two dyes, trypan red and methylene blue, the latter which was identified as a possible treatment for malaria. However, methylene blue was still less effective than the reigning antimalarial of the day, quinine from the bark of cinchona trees, which in turn was supplanted in the mid-twentieth century by the discovery of chloroquine and hydroxychloroquine [6].
Even so, neither chloroquine nor hydroxychloroquine would fit the true definition of a magic bullet or torpedo, as they both came with a bevy of known adverse effects ranging from most commonly, itching, headaches, dizziness and stomach upset, to most seriously, fatal heart failure and irreversible vision damage. Both drugs additionally have narrow therapeutic windows and long half-lives, making careful dosing crucial in avoiding life-threatening side effects [7].
Trump was correct when describing hydroxychloroquine as “one of the biggest game changers in the history of medicine," but not for its potential in COVID-19 treatment as the President claims. Rather, chloroquine and hydroxychloroquine were essential to the modern treatment of malaria, preventing Allied troops from being decimated by the tropical disease during WWII, when Axis occupation of the South Pacific led to a shortage of cinchona-derived quinine. Despite the revolutionary nature of chloroquine and hydroxychloroquine, malaria in the United States was not eradicated by a miracle drug, but by public health measures. Established in 1947, the National Malaria Eradication Program’s coordinated federal and state effort to distribute mosquitocides across endemic areas was what finally led to the elimination of malaria in the United States [8].
Of course, when considering infectious disease epidemics, what comes to mind is usually not malaria, but the much more recent HIV/AIDS epidemic. Yet the promise of a single magic bullet did not deliver in that crisis either. Azidothymidine (AZT), the first FDA approved drug for AIDS, was heralded as the light at the end of the tunnel when initial efficacy trials showed promising results. Pressure from activists and growing desperation from the public led to AZT being fast-tracked for approval despite major issues with the efficacy trials [9]. Similar to how Ehrlich promoted Salvarsan as a “magic bullet” and downplayed its myriad side effects, the company responsible for AZT routinely played up studies with positive results and excused those that showed potential negative results [10].
Patients who bought into the myth of AZT as a miracle cure suffered through chronic headaches, nausea, and muscle fatigue, only to face disappointment when later trials showed no significant differences in mortality between the drug and placebo groups after three years [10]. Even Dr. Jerome Horwitz, the scientist who first discovered AZT, acknowledged that the drug only “buys time” for patients [11]. Though it paved the way towards the newer combination therapies that have changed AIDS from a death sentence to a manageable chronic condition, AZT was not the cure people were hoping for in 1987.
Absent a cure, public health efforts have proven to be critical in preventing and limiting HIV outbreaks, even to this day [12]. While national rates of HIV have declined, opposition to such efforts have led to outbreaks, including one in Indiana in 2015. The state’s strict drug policies made needle exchange programs illegal, despite numerous studies indicating needle exchange programs do not increase the incidence of drug use [13]. It took two months of convincing by county, state, and federal officials for the then governor (now current Vice President and head of the US coronavirus task force) Mike Pence to sign an executive order allowing the distribution of clean syringes [14].
Today, as the result of the US sluggish response to the coronavirus pandemic, the Trump administration is facing similar criticisms to those levelled against the Reagan administration during the height of the HIV/AIDS crisis. The public is once more anxious and increasingly desperate for the hope that a cure can bring. Yet as history has shown, this is when responsible messaging is more important than ever.
Similar to Salvarsan and AZT, hydroxychloroquine is being hailed as a miracle cure for COVID-19. The scientific community’s concerns about the validity of Dr. Didier Raoult’s highly controversial study, which boasted a 100% cure rate using hydroxychloroquine, deterred neither Trump’s effusive praise of the drug nor various media outlets’ promotion of the study [15]. On Tucker Carlson Tonight, guest Gregory Rigano, a self-described “Stanford University Medical School advisor” (an affiliation that Stanford has denied), even made the claim that hydroxychloroquine is “the second cure to a virus ever” based on Raoult’s results [16]. Carlson perhaps most aptly tapped into our collective desire for a magic bullet with his reply, “Of course, it's our job to be skeptical of all and any claims. However, I very much want to believe this.”
Trump’s stance starkly contrasts with director of the National Institute of Allergy and Infectious Diseases and member of the US coronavirus taskforce, Dr. Anthony Fauci’s staunch refusal to promote the drug [17]. Notably, Fauci, who helped loosen FDA regulations that prevented many patients from participating in experimental drug trials during the HIV/AIDS epidemic, has been cautious on hydroxychloroquine due to the lack of definitive studies on the drug.
Dr. Monica Green, a noted medical historian, compared Trump’s evaluation of hydroxychloroquine to those of medieval doctors, commenting that “in the eleventh and twelfth century, the main way to validate the utility of a remedy was to say that it came from a very learned authority.” Indeed, this mindset, borne from a time before modern pharmacology or even the scientific method, seems to be pervasive in the administration. Trump’s economic advisor Peter Navarro said on Fox & Friends, “I think history will judge who’s right on [hydroxychloroquine], but I’d bet on President Trump’s intuition.”
President Trump and Peter Navarro may still have a chance of ending up correct. However, the chances are increasingly slim, as on April 24, the FDA issued a warning against widespread use of hydroxychloroquine or chloroquine for COVID-19 due to reports of serious arrhythmias. The FDA’s bulletin states, “Hydroxychloroquine and chloroquine have not been shown to be safe and effective for treating or preventing COVID-19” [18].
If it ultimately turns out that hydroxychloroquine is not effective for COVID-19, it will join the ranks of many other drugs that were promoted as miracle cures, but instead left a trail of dashed hopes and unmet expectations. More than a century after Huxley first spoke of a “cunningly-contrived torpedo” and despite decades of scientific progress since, we remain spellbound by “magic bullet” narratives. As we all do our part in maintaining the public’s health through social distancing and rigorous handwashing, we must also remain clear-eyed about the limitations of any drug promoted as a cure at this stage of the pandemic.
ACKNOWLEDGMENTS
We were lucky to also get the insight of medical historians Dr. Aaron Shakow of Harvard, Dr. Monica Green of Arizona State, Dr. Adia Benton of Northwestern, and Dr. Amanda Mahoney and Dr. Erin Lamb of Case Western in the formulation and execution of this piece.
REFERENCE
Quotes from medical historians were through personal correspondence.
Hamblin J. Why Does the President Keep Pushing a Malaria Drug? The Atlantic Magazine 2020.
Magagnoli J, Narendran S, Pereira F, Cummings T, et al. Outcomes of hydroxychloroquine usage in United States veterans hospitalized with Covid-19. Unrefereed preprint. medRxiv 2020.04.16.20065920; doi: https://doi.org/10.1101/2020.04.16.20065920
Huxley T. An Address on the Connection of the Biological Sciences with Medicine. Br Med J 1881;2:273
Heynick F. The original ‘magic bullet’ is 100 years old. Br J Psychiatry. 2009 Nov;195(5):456. doi: 10.1192/bjp.195.5.456.
Brandt A. No Magic Bullet: A Social History of Venereal Disease in the United States Since 1880. Enlarged ed. USA: Oxford University Press, 1987.
Krafts K, Hempelmann E, Skórska-Stania A. From methylene blue to chloroquine: a brief review of the development of an antimalarial therapy. Parasitol Res. 2012 Jul;111(1):1-6. doi: 10.1007/s00436-012-2886-x.
Browning DJ. Pharmacology of Chloroquine and Hydroxychloroquine. In: Hydroxychloroquine and Chloroquine Retinopathy. Springer, New York, NY, 2014.
Elimination of Malaria in the United States (1947-1951). CDC. (Accessed April 15, 2020, at https://www.cdc.gov/malaria/about/history/elimination_us.html.)
Park A. The Story Behind the First AIDS Drug. Time Magazine 2017.
Garfield S. The rise and fall of AZT: It was the drug that had to work. It brought hope to people with HIV and Aids, and millions for the company that developed it. It had to work. There was nothing else. But for many who used AZT - it didn't. The Independent 1993. (Accessed April 15, 2020, at https://www.independent.co.uk/arts-entertainment/the-rise-and-fall-of-azt-it-was-the-drug-that-had-to-work-it-brought-hope-to-people-with-hiv-and-2320491.html.)
Concorde Trial. National Institute of Allergy and Infectious Diseases. (Accessed April 15 2020, at https://aidsinfo.nih.gov/news/5/concorde-trial.)
Peters PJ, Pontones P, Hoover KW, et al. HIV Infection Linked to Injection Use of Oxymorphone in Indiana, 2014-2015. N Engl J Med. 2016 Jul 21;375(3):229-39. doi: 10.1056/NEJMoa1515195.
National Research Council (US) and Institute of Medicine (US) Panel on Needle Exchange and Bleach Distribution Programs, Normand J, Vlahov D, et al. The Effects of Needle Exchange Programs. In: Preventing HIV Transmission: The Role of Sterile Needles and Bleach. National Academies Press, Washington, DC,1995.
Twohey M. Mike Pence’s Response to H.I.V. Outbreak: Prayer, Then a Change of Heart. New York Times 2016.
Voss A. Official Statement from International Society of Antimicrobial Chemotherapy (ISAC): Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial (Gautret P et al. PMID 32205204). (Accessed April 15 2020, at https://www.isac.world/news-and-publications/official-isac-statement.)
Robins-Early N. The Hucksters Pushing A Coronavirus ‘Cure’ With The Help Of Fox News And Elon Musk. Huffington Post 2020.
Cohen E, Bonifield J, Nigam M. Trump says this drug has 'tremendous promise,' but Fauci's not spending money on it. CNN 2020.
FDA cautions against use of hydroxychloroquine or chloroquine for COVID-19 outside of the hospital setting or a clinical trial due to risk of heart rhythm problems. FDA. (Accessed April 26, 2020, at https://www.fda.gov/drugs/drug-safety-and-availability/fda-cautions-against-use-hydroxychloroquine-or-chloroquine-covid-19-outside-hospital-setting-or.)