The 1889 Russian Flu was the first influenza pandemic in an increasingly globalized world. In this episode, the second of a two-parter on how hydroxychloroquine became a great hope in COVID-19, we’ll talk about how quinine became the standard of care for influenza. Along the way, we’ll discuss the astrological origins of the flu, the nosological difficulties of identifying past pandemics, conspiracy theories about previous global coronavirus outbreaks, the media panic over the Russian Flu, first year law school cases about Carbolic Smoke Balls, and the first studies into quinine’s efficacy in influenza.
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3. Ewing, E. T. La Grippe or Russian influenza: Mortality statistics during the 1890 Epidemic in Indiana. Influenza Other Resp 13, 279–287 (2019).
4. Gold, E. Pandemic Influenza 1700-1900: A Study in Historical Epidemiology. Jama 257, 2656–2656 (1987).
5. Rice, G. W. & Palmer, E. Pandemic Influenza in Japan, 1918-19: Mortality Patterns and Official Responses. J Jpn Stud 19, 389 (1993).
6. Mulder, J., Masurel, N., Deggars, E. M. & Webbers, P. T. PRE-EPIDEMIC ANTIBODY AGAINST 1957 STRAIN OF ASIATIC INFLUENZA IN SERUM OF OLDER PEOPLE LIVING IN THE NETHERLANDS. Lancet 271, 810–814 (1958).
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11. When early modern Europe caught the flu. A scientific account of pandemic influenza in sixteenth century Sicily. (n.d.).
12. Potter. A history of influenza.
13. Valleron AJ et al, Transmissibility and geographic spread of the 1889 influenza pandemic. PNAS May 11, 2010 107 (19) 8778-8781
14. Cavallaro JJ and Monto AS. Community-wide Outbreak of Infection with a 229E-like Coronavirus in Tecumseh, Michigan.The Journal of Infectious Diseases. Vol. 122, No. 4 (Oct., 1970), pp. 272-279
15. Mulder J and Masurel N, Pre-epidemic Antibody Against 1957 Strain of Asiatic Influenza in Serum of Older People Living in the Netherlands. Lancet. 1958 Apr 19;1(7025):810-4
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17. Saunders-Hastings PR and Krewski D. Reviewing the History of Pandemic Influenza: Understanding Patterns of Emergence and Transmission. Pathogens. 2016 Dec; 5(4): 66.
18. Pappas G et al. Insights into infectious disease in the era of Hippocrates.International Journal of Infectious Diseases Volume 12, Issue 4, July 2008, Pages 347-350.
19. Flint A, Principles and Practice of Medicine. https://collections.nlm.nih.gov/bookviewer?PID=nlm:nlmuid-100894695-bk#page/234/mode/2up/search/influenza
20. Osler W, Principles and Practice of Medicine. https://archive.org/details/principlespract00osle/page/1002/mode/2up
21. Taubenberger JK and Morens DM. Influenza: The Once and Future Pandemic. Public Health Rep. 2010; 125(Suppl 3): 16–26.
22. Shope RE. Influenza: history, epidemiology, and speculation. Public Health Rep. 1958 Feb; 73(2): 165–179.
23. Ewing ET. Will It Come Here? Using Digital Humanities Tools to Explore Medical Understanding during the Russian Flu Epidemic, 1889–90. Med Hist. 2017 Jul; 61(3): 474–477.
Please note that the transcript is based off the editorial copy of the script rather than the actual episode.
This is Adam Rodman, and you’re listening to Bedside Rounds, a monthly podcast on the weird, wonderful, and intensely human stories that have shaped modern medicine, brought to you in partnership with the American College of Physicians. This episode is called “La Grippe,” and it’s an exploration of the 1889 influenza pandemic, and how quinine emerged as one of the most popular treatments. I originally started this series as a “short” intended to be only about 15 minutes looking into the history of using hydroxychloroquine in treating COVID-19. But telling that story quickly metastasized into what is turning into a three hour monster. In the last episode, I traced the development of quinine, starting in the pre-Columbian jungles of the New World, and ending in 1889, as germ theory was upending our understanding of both malaria and influenza, and the world was on the verge of the first “globalized” influenza pandemic. This episode will pick up there, with the 1889 “Russian” or “Asiatic” flu — but we’re taking anything but a straight course! We’re going to discuss the astrological origins of the word “influenza,” the nosological difficulties of identifying past pandemics, conspiracy theories about previous global coronavirus outbreaks, the media panic over the Russian Flu, first year law school cases about Carbolic Smoke Balls — and that’s all before we get to quinine! So let’s get going!
I’m finishing up this draft in June of 2020, as protests against racism and police brutality after the murder of George Floyd have continued to spread not only across America, but across the world. There’s a COVID-19 pandemic, but I also think it’s fair to say that these marches are against an equally deadly pandemic of structural racism. I went to medical school at Tulane in New Orleans, and I remember one of the most shocking news stories to come out while I was there was a zip-code mortality analysis that showed that the average life expectancy in 70112 — the overwhelmingly black neighborhoods of Treme and Midcity — was just 54, compared to 70124, the Lakeview neighborhood, where the life expectancy was 80 (https://www.nola.com/entertainment_life/health_fitness/article_e55b4b16-4752-5c16-914b-854d7c563d85.html). That’s comparable to the worst of the AIDS epidemic, similar to tiny Lesotho where the prevalence is almost a quarter of adults, or war-torn Somalia. So let’s talk about the word pandemic and epidemic. The words have specific definitions today — the CDC for example, defines epidemic as “an increase, often sudden, in the number of cases of a disease above what is normally expected.” A pandemic, if you remember those quaint days when we were waiting for the WHO to declare a COVID-19 pandemic, is an epidemic spreading over national borders to become a global phenomenon. As you can imagine, these terms usually get used for infectious diseases where vectors are much clearer — COVID-19, and before that the H1N1 swine flu, but they’re also used for chronic diseases with complex societal and physical etiologies, like the opioid epidemic, the obesity epidemic, and like we’re starting to discus, a racism pandemic.
But this is not the traditional definition of epidemic (pandemic is a modern word, taken off of epidemic). Just like “fever” and “malaria,” epidemic is a word that has been used to describe different concepts in very different epistemes. So to understand early influenza epidemics — really, to understand the early modern concept of “influenza”, we need to take a trip back to the fifth century BCE to talk about a little book called the Epidemics. The Epidemics are a series of books ascribed to Hippocrates — the first and third might actually be by him, but the remainders are likely by a second (or multiple) authors. I’ve talked about the Epidemics in several different episodes, not because I’m deeply fascinated by ancient medicine, but because they’re essentially the medical journal of a physician travelling across the Aegean, documenting what he saw as he went. The authors use simple, descriptive language to describe the lives and afflictions of their patients; there’s something deeply human about reading case notes from patients who lived 2500 years ago.
The Greek root is fairly simple — epi, or on, and then demos, people, or country. Homer had used this word two centuries before as an adjective to mean someone who is in his own country, as opposed to a traveler. By the time of Hippocrates, the word essentially meant, “that which circulates in a country” — which could mean groups of people, weather, rumors, or war.
The Hippocratics took this pre-existing word and transferred it to disease. To be clear, there were already plenty of Greek words for disease. The most popular one is probably “nosos,” literally disease, and the root of that I say literally every episode, “nosology,” the classification of disease. So how was an epidemic different? The Hippocratics made a very valuable observation — there appeared to be groups of diseases — nosos — that would circulate in a given time period. These “syndromic groupings” seemed, to the Hippocratics, to be influenced by the positions of the stars, atmospheric conditions, and geography. They were “the disease which circulates in a country” — hence, epidemics.
The classic example is the cough of Perinthus described in Epidemics VI — a season-long syndrome of “sore throat, leg paralysis, peripneumonia, problems with night vision, voice problems, difficulty swallowing, difficulty breathing, and aches.” This constellation of symptoms has been proffered as the first description of influenza, though paleopathologists and medical historians have also offered up diphtheria, encephalitis, dengue, and polio, among others. The challenge, of course, is that we’re projecting the modern word epidemic onto the past. The Greeks would have had no problem accepting that many different diseases could have caused these presentations — but they would have all been influenced by a common condition.
This would have been in contrast to plague, generally described using the word nosos in Greek, or in Latin pestis. Take the Plague of Athens, for example, which Thucidydes described during the Second Peloponnesian War, and which was estimated to have killed a quarter of the population. This language suggests a single cause. And for millennia, essentially until we reach the modern era, this distinction remained in place.
It’s with this framework we have to consider the disease “influenza” — originally described not as a single transmissible disease, but as a collection of symptoms caused by environmental factors, and in particular by the arrangement of the stars and planets. The name “influenza” comes from Italian via Latin — “ab occulta quadam coeli influentia,” or influence through atmospheric phenomenon, though more accurately (and far more mysteriously) would be “influence through the astral plane”. And it’s that seemingly astral influence — that the disease would strike seemingly randomly ever several decades or so many places at almost the same time — that was the defining characteristic. You can tell this from many of the names the disease has had over the centuries — horion, meaning “blow or stroke,” the “lightning cattarh,” and probably the most popular name until the early 20th century in English, and still the preferred name in France “la grippe,” from French to “attack.”
In 2020, though, we have a very different conception of the disease, and I think it’s helpful to explicitly discuss this so as to avoid some confusion going forward. Our disease influenza is caused by a virus in the orthomyxovirus family — imagine a beach ball concealing its pressure RNA inside, surrounded by little spikes of hemagglutinin and neuraminidase proteins. It’s primarily a respiratory virus, transferred from the coughs, sneezes, and breathing of infected individuals. Influenza causes symptoms much like any other respiratory virus, but is far more severe — patients have a rapid onset of an often high fever, with severe muscle aches and fatigue, which usually lasts for several days. That being said, the disease is generally mild, causing deaths in elderly and ill patients, but it has a dramatic reach — each year, the WHO estimates that there are one billion cases of the disease, 3-5 million severe cases, and 300k – 650k deaths, often from an associated bacterial pneumonia (classically staph aureus).
I don’t want to get too much into molecular biology here, but what makes influenza so interesting is those spikes on the beach balls — neuraminidase and hemagglutinin. Both of these proteins evoke a humoral immune response in humans; that is, we make antibodies to these proteins to fight the virus off. But RNA viruses are notorious for mutations, and both hemagglutinin and neuraminidase slowly accrue mutations over time. This results in a stepwise decrease in immunity over time, resulting in seasonal spread of the flu (and why new flu vaccines must be developed each year). But sometimes new strains will arise with a completely different hemagglutinin molecule — there are 16 combinations in total, titled H1 through H16. This is termed “antigenic shift” rather than drift. And when conditions are perfect — this mutation happens in a specific geographic region amenable to its spread, there have been no strains circulating in the past few years that might confer some degree of immunity, this strain has mutations that allow for easy spread and high morbidity and mortality — an influenza pandemic is launched. Because all of this happens on a fairly predictable schedule, influenza pandemics occur about every 50 years or so. These pandemics can have massive mortality — allowing for difficulty in counting the dead in past pandemics, the 1918 flu may have killed 50 million people worldwide (and the world wide population was only about 1.5 billion at that time).
Almost immediately you can see an obvious difference in our modern definition — the idea of “seasonal flu” didn’t exist prior to the mid 19thh century or so. Influenza was what we would call epidemic or pandemic flu, and was characterized more by its rapid onset and characteristic spread. What we today call seasonal flu would have been one more “cattarh” or “cattarhal fever,” a generic winter-time respiratory disease that caused a fever, lumped in with any other number of viruses. We also don’t have a conception of how old the disease truly is. Potter performed a literature review of historians attempting to classify influenza pandemics from the historical record; the first likely description of influenza was probability in 1173, though not clearly a pandemic. And while there’s some disagreement about whether this one represented an epidemic or pandemic, I want to discuss the 1557 flu in the Italian states, because the descriptions are clearly recognizable to the disease we all know, and because it’s the first where where influenza is considered to be a contagion. I spoke about contagion in the ACP presentation I did with Tony on syphilis in episode 45.. Epidemic disease like the great syphilis outbreak of 1495 offered a challenge to miasmatic theories of disease — if disease occurred because of imbalances of the four humors, influenced by various environmental conditions, how would a large number of people get sick all at once? And syphilis, with its chancres on the genitals, offered a compelling case that some disease was transferred by touch. In 1548, Fracastoro published his On Contagion. His ideas are a little more complicated than they’re often described — I went into them in depth in episode 48 Micrographia — but briefly he suggested that disease could be spread from person to person, but also from intermediate objects called fomites.
The 1557 flu spread rapidly from Asia to North Africa, then into Europe so quickly that in Spain it was noted that “the greater part of the population in that Kingdom was seized with it almost on the same day.” Like I said, the symptoms are very recognizable to a doctor in 2020: quoting from Thomas Short, who described this “cattarhal fever” striking England: “A grievous pain of the head, heaviness, difficulty of breathing, hoarseness, loss of strength and appetite, restlessness, watchings, and a terrible tearing cough. Presently succeeding a chilliness, and so violent a cough, that many were in danger of suffocation.” While Short felt that few people died “except some children,” modern analysis of parish registries in England from this period suggest increased mortality.
In the Italian states, the 1557 flu offers the first “modern” view of the flu as an infectious disease, rather than a collection of related symptoms. Since the Black Death and subsequent plagues, Italy city-states had a designated “protomedicato” — a medical officer whose job was to safeguard the health of the entire population. You often hear about the word “quarantine,” coming from the Venetian tradition of isolating sailors of ships from plague areas for forty days. These policies would have all been enforced by the protomedicato. So in 1557, the Senate of the Kingdom of Sicily asked the Protomedicus G. F. Ingrassia what they should do about this influenza that was spreading rapidly. Ingrassia realized that this was a contagion like Fracastoro has described (he called it a pestilential fever), which just like the plague had to be treated on a population basis. In a public speech, he outlined his control regimen — it included very standard Galenic interventions, like cleaning the streets of dead dogs and other foul smells, burning large bonfires to clear the miasma, covering sewers, and providing good bread and meat to the people. But it also included “territorial control” — what we would now call “social distancing,” shutting off infected areas and instituting what would now be called a “cordon sanitaire”. And as a nice piece of perspective for my fellow citizens who are getting bent out of shape over being required to wear a cloth mask in public, the penalty for violating the territorial control was death.
After 1557, it becomes much easier to identify influenza pandemics in the historical record, and Potter identified 1580, 1729, 1781, 1830, 1898, 1918, 1957, and 1968. The review is before 2009, but that must be added as well. This analysis gives us a very interesting context to try and understand — and predict — future outbreaks. The time between the outbreaks varies between a decade and 50 years, holding to that for 500 years. His final words in the paper are eerily prescient. Using an average of 40 years between pandemics, he predicts that the next influenza pandemic will be by 2017, writing, “It is unrewarding to attempt to seek a pattern for pandemics which will allow predictions; but it is self evident from the history of pandemics that each year that passes brings the next pandemic one year closer.”
The spread of influenza pandemics appears to be very stereotyped as well. As he points out, all of the pandemics since 1557 originated in China, Russia, or Asia, before spreading via trade routes outwards. The reason: “It is in China, where one-quarter of the population of the earth live, and where ducks, pigs and humans live in the closest proximity and the highest density, that reassortment is most likely to occur; this correlates with the point of origin of pandemic viruses.”
If this sounds familiar to you, take a trip down the rabbit hole a little further with me. COVID-19, of course, is not influenza. It is caused by a novel coronavirus, SARS-CoV-2, novel in that it has not been seen before in humans. There are four routinely circulating coronaviruses that are generally lumped into the “common cold” — OC43, KHU1, 229E, and NL63. Furthermore, there are two additional, far more severe coronaviruses MERS and SARS. There’s little doubt in my mind that had COVID-19 struck prior to the identification of viruses, we would have called it influenza. It fits the general description — high fevers (though for a longer time than the flu), lower respiratory symptoms, malaise, GI symptoms, even some of the neuropsychiatric manifestations. How can we be sure that some of those past influenza outbreaks were not, in fact, coronavirus outbreaks? And that because the virus became endemic — and basically infects everyone when they are children now, conferring some degree of immunity — we have forgotten just how deadly the disease could be?
And here’s where things get interesting. In 2005, scientists sequined the complete genome of HCoV-OC43, one of the four “common cold” coronaviruses. By looking at mutations acquired since it diverged from a bovine strain, the researchers placed the date of cow-to-human transfer sometime in the late 19th century. This was the exact period, of course, of the 1889 “Russian Flu” pandemic. Reading through old descriptions of the Russian Flu, the similarities to COVID-19 are persuasive. For example, abdominal complaints were common, as was “delirium” and “psychosis” — newspaper reports were full of stories of suicides after the flu. Could the Russian flu have actually been an OC43 coronavirus pandemic? There are no samples of the 1889 virus left to analyze — and the difficulty in obtaining the H1N1 from the 1918 Spanish Flu suggest we’re probably not going to find any.
The greatest argument against this comes from a 1958 paper by Mulder, who collected 1256 blood samples from older people in the Netherlands aged 50-100. He found a huge spike in H2 — that is, one of the hemagglutinins — titers in patients clustering around the age of 80, essentially absent in patients below the age of 70. Similar antibodies had been seen in patients in the 1957 Asian Flu, H2N2. His conclusion: “This suggests that the 1957 pandemic of influenza was a repetition of an epidemic which appeared in the last quarter of the 19th century, and that this epidemic might well have been the pandemic of 1889-90, which also originated in Asia”
I’m not done inhabiting conspiracy theory territory yet. Using a similar methodology, researchers concluded that another coronavirus, 229E, came into origin right about the 11th century — so again, a possibility to have caused the influenza outbreak in 1173. All of this makes it sound like I browse PubMed with a tin foil hat on, but I truly think these studies raise compelling — and likely unanswerable — questions about coronavirus pandemics of the past.
With that conspiracy theory in mind, let’s talk about the Russian Flu of 1889. I argued that this was the first “global” influenza pandemic — not global because it traveled over the globe, since all pandemics by definition do that, but because its spread was breathlessly reported by newspapers, with reports being filed by telegraph. Just as had happened during the second cholera epidemic, doctors and the public alike tracked the almost daily spread of La Grippe, including wild rumors about the cause and spread, prejudices against certain ethnic groups (in my home of Boston, the Chinese community was targeted in particular), physicians dispensing public health and treatment advice, and opportunists trying to make a buck. That is to say, it was remarkably like Twitter and COVID-19 in 2020.
What did influenza mean for people as news of a pandemic started to circulate? Circa 1889 in the United States was a formative time in American medical history, in the midst of a transition to “scientific medicine.” So I decided to compare my two favorite textbooks, the sixth and final edition of “Principles and Practice of Medicine” by Austin Flint, published in 1886, the year he died. This was the definitive medical text of the mid 19th century. Flint writes: “For the last four or five centuries medical observers have noted the occurrence from time to time of an epidemic affection characterized by bronchitis. In most countries it is commonly known by the name influenza, after a term introduced by the Italian writers in the 17th century. In France it is called la grippe.” He is agnostic as to whether the disease is infectious or from an atmospheric cause, equally speculating that it might be “animalculae” (notably not using the word bacteria), or ozone in the atmosphere. He actually felt that ozone was more likely, since he recounts an outbreak at Mass General in which all the patients on the wards were affected. Treatment was with “diaphoretic remedies” and opium, but in the elderly he suggested supportive care and quinine.
In 1892 a new Principles and Practices of Medicine had been written for a new scientific medicine by William Osler. I personally own a facsimile of the second edition, which is why I always quote from that one on the show, but it’s basically the same as the first edition. And his article on influenza is far more familiar to us, containing insights from his own treatment of patients during the 1889 influenza. First he recognizes a more varied presentation, ranging from mild illness to “severe bronchitis, lobar and lobular pneumonia, and nephritis,” as well as heart failure, delirium, insanity, diarrhea, and GI symptoms, as well as myalgias as if “bruised and beaten.” Osler largely discounts a “meteorological condition” causing the disease, and feels that its presentation must be a “virus” (which at this point is essentially a synonym for bacteria). He discusses the theory that diplococcus pneumonia, now Strep. Pneumoniae, might be the cause, but pretty much dismisses it out of hand since it is so common in non-influenza pneumonias. He also makes the observation that the seasonal disease is the same as epidemic influenza, which had become very clear after the Russian Flu. Osler, who was characteristically conservative in medical therapy, actually recommends the new antipyretics like antipyrine and salicylic acids though in general urges restraint. This is a description of influenza that I think many of us recognize in 2020 — a seasonal and well an epidemic respiratory disease with a variety of other manifestations, dangerous especially to the elderly and those with chronic medical conditions, and in which supportive care, including with antipyretics, is the primary treatment (though we also some antivirals now, with admittedly limited effectiveness).
The start of the Russian Flu, or the Asiatic Flu, as it was sometimes known in the West, is still clouded in mystery. Finkler wrote in 1898 a description that still roughly holds today: it “broke forth from the East and overwhelmed the world in a pandemic such as had never before been seen. The high flood of the pandemic flowed over the whole globe in the space of a few months.” The first cases may have been seen in Bukhara, in modern day Uzbekistan, in Greenland, and on the Hudson Bay in Canada. In any event, by October of 1889, influenza was rampant in Siberia, and quickly spread west to European Russia. Apparently, according to a Dr. Turner, who treated the first Russian flu patient in England, the disease was called the “Chinese flu” in Russia — which would not be surprising if true, given our knowledge of historical outbreaks, nor would it be surprising if untrue, given a historical tendency to blame outsiders for epidemic disease. By November that year, the flu had spread to Western Europe. In 2010, researchers actually calculated how quickly the Russian flu traveled in a world newly linked together with railroads and steamships by looking at mortality records in cities across Europe and the United States.. The pandemic took only four months to spread across the globe; the time from the first detected “peak” in St. Petersburg to the peak in the United states was only 70 days; for what its worth, they also calculated the basic reproductive number, R0, and the case fatality rate, finding an R0 of 2.1, an a CFR from 0.2 to 0.3%. Overall, the speed was 300 km/week. It would be difficult to compare “peaks” in Wuhan and the United States for COVID-19 because of differing mitigation methods, but if we compare the first cases — December 31st in Wuhan, and January 20th in the US — you get 20 days. Which is faster, of course, but not remarkably so, given that we’re comparing airplanes and steamships,
As the disease reached the United States in December of 1889, newspapers anxiously speculated about the disease. There are far too many to adequately discuss, but I want to highlight a “digital humanities” analysis of a single article that shows the chaotic swirl of information, speculation, and fear. On December 28, 1889, Dr. Roberts Bartholow published an essay in Medical News called “The Causes and Treatment on Influenza” targeted towards a medical audience. There was nothing particular novel about the article — targeted towards physicians and pharmacists, he paints a description similar to Osler, describes the European experience with influenza, and finally lists therapeutics. The digital humanities approach, however, shows that within only a few days, Bartholow’s article had spread via wire service throughout the United States to at least 50 daily and evening newspapers, often accompanied by commentary from local experts. And as his story spread, some themes that might sound familiar to us in 2020 came up, like this editorial in the Sedalia Weekly Bazoo on the 7th of January, 1890:
“There seems to be an irresistible pensity, among certain newspaper writers, to try to create panics over the public health. They are never happy unless they can publish stories of fatal epidemic and disastrous plagues …Just now these panic-mongers are filling the papers with accounts of the ravages of influenza… The influenza] is probably not nearly so much to be feared as the remedies which Dr Bartholomew [sic] of Philadelphia recommends as safeguards: the inhalation of sulphuric-acid gas, five grains of chinoidin three times a day and two grains of calomel at night. A patient who survived these medicines need fear no epidemic in this world.”
So let’s talk about these two therapies — the inhalation of acid fumes, and “chinoidin”, which is an antiquated name for a mix of the alkaloids of cinchona (of which quinine was the most common).
Let’s start with the inhalation of phenol and vitriol — carbolic acid and sulphuric acid. This is one of those obscure facts from the 19th century that we could probably gloss over, except that “aromatic acid” was the cause of one of the most famous legal contract cases; apparently Carlill vs. the Carbolic Smoke Ball Company is one of the first contracts cases taught to first year law students, and in some ways is the first case of the law protecting consumers. I am completely out of my depth when reading articles in the legal literature. But I will say that most articles I read started by discussing with some incredulity the Carbolic Smoke Ball itself — a small rubber ball with a short tube filled with powdered carbolic acid. Looking like those bulbs we use to flush out earwax today, you’d insert it into your dose, give the bulb a little squeeze, and inhale deeply in a smoke of phenol, which could “positively cure”, according to the advertisement, “colds, asthma, bronchitis, hoarseness, loss of voice, influenza, croup, whooping cough, and of course, thighs being the late 19th century, “neuralgia.”
This seems like a load of quackery from the 21 century perspective — inhaling acid?! — but in 1890 it was, if not quite within the mainstream, adjacent to it. Lister had first used carbolic acid spray to prevent surgical infections in the 1860s, ushering in a new age of antisepsis, though it took decades to fully spread around the world. But prior to the widespread acceptance of germ theory, it wasn’t entirely clear just how carbolic acid prevented infections. The initial focus was, in fact, not on the surgeons’ tools, but on the surgical wounds themselves, which would receive a hefty spray of phenol. And it is perhaps not too much of a stretch that if phenol in wounds seemed to work, perhaps by inhaling it it might cure respiratory disease? By 1892, with germ theory ascendent, and hand washing and surgical gloves starting to be used, this all seemed a bit quaint. But in that second edition of Osler I keep using, he still recommends “aromatic sulphuric acid” for night sweats in tuberculosis, “purpura hemorrhagica,” which would now be considered TTP and/or DIC, pulmonary hemorrhage, and even heart attacks. And carbolic acid gets an even warmer welcome, though usually ingested. But for both pneumonia and chronic bronchiectasis, what we would today call COPD, Osler warmly speaks of inspiration from a a steam atomizer full of carbolic acid
All of this is to say, when in the midst of the Russian Flu on November 13, 1891, when the Carbolic Smoke Ball Company placed an advertisement in the Pall Mall Gazette, filled with testimonials from aristocrats, claiming that a “£100 reward will be paid … to any person who contracts the increasing epidemic influenza colds, or any disease caused by taking cold, after having used the ball three times daily for two weeks, according to the printed directions supplied with each ball,” and showing that 1000 GBP was placed in a bank to show the company’s “sincerity,” it was hardly an absurd idea that the smoke ball might work.By the way, according to the Bank of England’s inflation calculator, that comes out to almost 13,000 pounds today, or 16k USD. A Mrs Louisa Elizabeth Carlill bought one of the smoke balls and used it religiously for two months until she fell ill with the flu. She naturally tried to collect the hundred pounds, but the company ignored her. Fortunately for her, she was married to a lawyer, and he brought a case arguing that their advertisement had in fact been a contract. The Queen’s Bench decided for her, setting a sweeping precedent. Which, honestly, I don’t really understand all the implications here, but according to Wikipedia at least, it was cited in the 1999 American legal case Leonard v Pepsico, Inc, where a man attempted to redeem seven million Pepsi points in exchange for a Harrier jet. So there’s that.
Okay, that tangent went on way too long, but I think the overall point stands — in the setting of a global media frenzy, public panic, and legitimate medical confusion about the cause and treatment of the disease, a panoply of treatments were thriving. But pretty quickly, one therapy emerged as the go-to to both prevent and treat influenza — so much so that druggists across America reported running out. And that, of course, is quinine. I’ve posted an absolutely amazing cartoon from the January 12, 1890 Parisian magazine Le Grelot entitled “Everyone has influenza!” It shows a macabre dance, a doctor leading a patient in the center, surrounded by skeletal musicians, and finally a circle of doctors and pharmacists dancing joyously with two women labeled “antipyrine” and “la quinine”. Antipyrine was, as you can imagine from the name, was one of the first of the new class of drugs called antipyretics; it’s still made today, though as a reference standard for hepatic metabolization of other drugs.
That quinine was used so readily should not be particularly surprising. A quick review of last episode — we think of quinine and its derivatives as primarily antimalarials, but also as immunomodulators for some rheumatologic conditions, but it was a bit more nuanced than that in the late 19th century. While malaria had been essentially redefined as a periodic fever which responds to quinine, the mechanism by which the drug worked was still mysterious.
If miasma (or “local conditions”) were the cause, quinine presumably worked by interrupting some periodic effect on the body. This is probably the reason quinine was used in treatments as varied as hemorrhoids and ulcers — both seemingly occurred on some sort of pattern. From this logic, it’s not too much of a stretch to look at a febrile influenza pandemic striking every several decades and recurring for a year or two and thinking that the drug might have some effect.
By the late 19th century, both in Europe, England, and North America, the idea of efficacy had become widespread — that therapeutics needed some sort of experimental justification in order to know that they worked. “Justification” looked very different in the 19th century than it does today, where clinical trials Take, for example, oseltamivir, originally developed from an extract of star anise to treat influenza. These studies enrolled 1400 people at a multitude of different sites across the world. I have no idea how much it cost, but the media stage III trial apparently costs 19 million dollars. And even then, it doesn’t actually work that great to treat the flu!
Trials looked very different in the 1890s — and doctors did not agree. I’m going to reference competing studies in the British Medical Journal as an illustration of the medical debate on this topic — but it’s also important to note that regardless of what medical professionals felt, quinine was widely available to the general public from druggists, as part of patent medications, and dissolved in various beverages, usually wine.
On April 6th, 1895, a Dr. Coghill wrote a piece extolling the virtues of quinine in preventing influenza. He first noted what had become very clear — that the Russian flu continued to circulate on an annual, seasonal basis, though less severe with each passing year. This fact — that influenza was not a “one time event” — led to an imperative to discover some sort of prophylaxis. Coghill had no doubt in his mind: “in my experience in this connection has confirmed the opinion hat in quinine we have an almost exceptionable preventive of the scourge.”
Coghill then described an experiment that he carried out in 1891, in which he was consulted by the leaders of a boarding school in England. Just like many school systems in 2020 with COVID-19, the leaders of the school had a pertinent question — should they close it to protect the pupils and staff? Instead, Coghill proposed an experiment. He prescribed a five grain pill of quinine — that is, the standard malaria dosing, 325 mg — to every boarding student, 19 in total. The day students and staff did not get the prophylaxis. None of the boarding students fell sick, despite sick staff members and day students. Based on this, he put his entire household — 14 people in total — on quinine prophylaxis. Only one member of his household ended up getting the flu, which pretty much proved the old aphorism true — he who acts as his own doctor has a fool for a patient. Only Coghill became ill with influenza pneumonia of the right lung and high fevers up to 103.8, when he forgot to take quinine prophylaxis for several days. He also noted that quinine seemed to work as a treatment — influenza patients seemed to defervesce faster with quinine than what he termed “so-called anti-pyretics.”
One of the reasons I love old medical journals is that the correspondence can be so, let’s just say, salty compared to what gets published in letters to the editor today. It’s kind of like Medtwitter, except you’re required to call everyone “sir.” So the next month, a Dr. Childe dunked on Coghill by describing two experiments he had performed: the first was a large family who had requested prophylaxis with quinine against Childe’s advice, and in whom all but one person became ill with influenza. The second was a boarding house of 51 people which he oversaw in which no one became ill despite a severe outbreak of the flu. “If they had taken quinine,” he wrote, “it would have been natural enough to ascribe their immunity to the drug, and equally erroneous.” Personal anecdotes were far too fickle, he argued, and there appeared to be only one treatment to stopping outbreaks: “I believe that the true prophylaxis of influenza consists, as in other highly infectious diseases, not in any specific drug, but in early and effectual isolation of the infected person.”
So that is where this episode will end, dear readers. By the 1890s, quinine, both as a treatment and a prophylactic for influenza, had become widespread. But doctors certainly disagreed about its utility, and moreso about what would even constitute appropriate evidence. So remember how I promised last episode that Dr. Rahul Ganatra would join in for a discussion bringing the debate all the way up to 2020 and COVID-19? Well, because I can’t help myself, that will be pushed off to next time, when we talk about chloroquine, epistemology, the deep tentacles of historical practice, and COVID-19!