Fever Dreams

Sadly, this year there were no Nobel Prizes awarded for any work on microbes - infectious or non-infectious. However, in celebration of the Nobel season, I wanted to take you back to 1927, when an interesting Nobel Prize in Physiology or Medicine was awarded to one Julius Wagner-Jauregg.

I was reminded of this particular Nobel Prize at a ballet I attended on the weekend. I went to see the Dutch National Ballet perform 'Mata Hari', inspired by the Dutch exotic dancer, courtesan, and World War I spy of the same name. Mata Hari, born Margaretha Geertruida MacLeod in Leeuwarden, the Netherlands, 1876, was the epitome of "live fast, die young". Her story is fascinating - both inspirational and sad. If you do read up on her story, you will find that both of her children died young - likely due to complications from the syphilis infections that they inherited from their parents.

At the turn of the 20th century, syphilis was indeed still a matter of life or death. An infection with the bacterium that causes it, Treponema pallidum, would start relatively small and localized. First, people would notice skin lesions - nasty blisters that are highly infectious - which would then fade away as the patient developed some immune response against the bacterium. If this infected historical citizen were lucky, they would then enter and remain in the so-called 'latent' phase of syphilis, where their own immune system would be able to keep the bacterium in check. They would have the infection, but they just wouldn't really notice the bug. On the other hand, if they were unlucky, that latent phase would eventually come to an end, and things would get much, much worse.

If their immune system came to the point where they couldn't keep the Treponema pallidum at bay any longer, the bacterium would come back with a vengeance. And thus, the 'tertiary phase' of syphilis infection would begin. The bacteria would spread out through the body, to destroy the skin, bone, cartilage, heart, eyes, and nervous system. As the nervous system - including the brain - deteriorated, the historical diagnosis at this point would be 'general paralysis of the insane'. As the nervous system was slowly destroyed by the invading bacteria, the patient would start to have a host of unpleasant symptoms, including personality changes, mood swings, memory problems, lapses in judgement, and eventually even delusions, dementia, and seizures.

In the early 19th century this 'madness' was attributed to 'a dissolute character', or as I would put it, 'having too much fun'. But, thanks to the dedicated work of early microbiologists, the true cause of these severe symptoms was eventually correctly identified to be bacterial.

So then, the next question was: if it is indeed infectious, then how do we cure it?

Many minds applied themselves to this problem. Now, some of the proposed cures might sound outrageous - but keep in mind that the goal at the time was purely not to die of syphilis. Side effects were better than certain, painful, drawn-out death. For instance, early proposed medications were things like mixtures of iodine and mercury, or Salvarsan, an organoarsenic compound. Although, come to think of it, perhaps people would still take that one, seeing as it's ORGANIC arsenic. As a side note, therein lies a lesson: not everything that is organic is good for you. In this case, 'organic' just means it has carbon molecules in it. It will still make you vomit. But nonetheless - nausea was preferable to certain death.

However, there was something that worked even better than organoarsenics or mercury: malaria.

That's right, you read it correctly. Malaria.

Julius Wagner-Jauregg was awarded the 1927 Nobel Prize in Physiology or Medicine for his work on 'pyrotherapy' - i.e. 'fever therapy', or more specifically, 'The Treatment of Dementia Paralytica by Malaria Inoculation'.

The leading hypothesis to explain how this pyrotherapy works is simple: the patient's body becomes hot enough due to the repeated high fevers caused by the malaria parasite, that Treponema pallidum simply can't take the heat. In other words, the body's response to malaria also kills off the bacteria - if one is lucky.

Wagner-Jauregg came upon this idea by observing his patients in an asylum in Vienna. He noticed that several patients with bad cases of typhoid or other feverish infectious diseases sometimes recovered from their severe mental illnesses upon recovering from the fever. Wagner-Jauregg wasn't the only one to notice this - but he was one of the most dedicated ones in systematically following up on the observation. He soon began to search around for the best, and safest, way to induce fever, in order to cure patients of tertiary syphilis.

By our standards, some of his actions were questionable. I mean, by this point, you already know that this story ends with him infecting people with malaria in order to cure them of syphilis. But, at the time, this guy was trying to do right by his patients - to find a cure within his current knowledge and means. As well as malaria, he also attempted to treat patients with pyrotherapy using tuberculin (a protein isolated from the bacteria that causes tuberculosis), streptococci (another type of infectious bacterium), and even vaccines that could cause short-lived but relatively safe fevers. But malaria was, time and time again, the winner in terms of safety and effectiveness in curing tertiary syphilis.

You might be thinking, what?? How is malaria safe? Didn't a new vaccine against malaria just come out, which is expected to save hundreds of thousands of lives every year?

Well, again, the question is of relative safety. In the early 1900s, when Wagner-Jauregg was operating, the richer people of the world already had access to quinine sulfate, a drug that can successfully treat malaria. After the malaria-treated syphilis patients had experienced a handful of high fevers, they would be treated with quinine sulfate, and, oftentimes then both the malaria and the syphilis would be gone. In other words, being infected with malaria was an acceptable risk to take in the eyes of Wagner-Jauregg and his patients.

Now, this story is also one to show how far we have come. Fever therapy was phased out with the discovery of the first antibiotic, penicillin, which was a much safer way to treat syphilis than being infected with a parasite.

Medicine moves on with the times. In medicine and science, we are constantly working with whatever material is the best that we have at the time. We strive to both learn more, and to put what we learn into practice. As a result, guidelines change as we gain insights - and typically that means improvements in practice and understanding overall.

In other words, I hope that this story serves as another explanation for why scientists change their minds upon finding new information. As happy as I am that we've moved onto penicillin to treat syphilis and vaccines to prevent malaria, rather than using one to treat the other, I also understand that the doctors of the last century were doing their best within their current constraints.

Until next time, I'll leave you with a question - has anything changed your mind today? Or what would it take to change it?

~ Alex

P.S. Due to the Microbial Mondays web-host, being down last week, this article was originally posted here.