The Epidemiology of Greyscale

[Obvious warning is obvious: potential spoilers for A Song of Ice and Fire novels/Game of Thrones TV series below].

While no one will claim that George R.R. Martin’s epic series, “A Song of Ice and Fire,” is historically accurate, there are a number of historical parallels that can be drawn from the characters and plotline–particularly from medieval Europe. While most of those relate to epic battles or former monarchs or other royalty, another of Martin’s characters, so to speak, is the disease greyscale (1).

Greyscale is a contagious disease that seems to come in at least two distinct forms: greyscale, an endemic and slow acting, highly contagious illness that can affect either adults or children; and the grey plague, a rapidly-spreading epidemic that can wipe out entire swaths of cities in a short period of time. Both versions of the illness have a high fatality rate (no exact details are given, but it seems to be close to 100%, especially in adults). Recovery from greyscale makes one immune to outbreaks of grey plague, so they seem to be caused either by the same microbe or ones which are very closely related.

The Epidemiology of Greyscale

Greyscale is a disfiguring disease. As its name suggests, it transforms the skin into a hardened, scaly tissue. As the skin dies, it becomes grey in color with permanent cracks and fissures. Infection that spreads across the face can cause blindness.

Like many diseases we consider to be “childhood” diseases (measles, mumps, smallpox, chickenpox, etc.), children seem to be spared the worst of the disease and are the most likely to recover from the illness, though recovery still appears to be quite rare. The disease is most common in Essos, but can also be found occasionally throughout Westeros, including north of the Wall (more on that below).

Greyscale is believed to be transmitted primarily person-to-person via direct skin contact. We see this in the books with the infection of Jon Connington and on the TV show with Jorah Mormont, as both characters are transporting/protecting Tyrion Lannister and apparently are exposed to the pathogen during a battle with the Stone Men (2, 3). The Stone Men are victims in the last stage of greyscale infection, where the skin is entirely calcified and there is involvement of muscle, bone, and internal organs, including the brain. Late signs of greyscale infection include violent insanity, leading sufferers to violently attack anyone who comes near. As these Stone Men are highly feared as sources of the disease, greyscale appears to be contagious for the entire duration of infection, from the development of symptoms to near-death.

A Stone Man with late-stage greyscale infection.

If a person has been exposed to greyscale, but is not yet showing symptoms, they can check for impending infection by pricking their toes and fingers each day. Once they’re no longer able to feel the knife, that’s bad news–greyscale infection is likely, as insensitivity to touch is one of the early signs. Once the scaling begins, the victim no longer feels any pain in the affected areas, making the Stone Men essentially invulnerable to pain.

The incubation period of greyscale seems to be very short. As soon as Jorah and Tyrion realize they are safe and the Stone Men are defeated, Jorah rolls up his sleeve and we see that the initial small patch of greyscale has already appeared.

First appearance of Jorah’s greyscale following fight with Stone Men.

Another prominent victim of greyscale, Shireen Baratheon, is thought to have acquired greyscale via contact with a fomite (an inanimate object that serves as a vehicle to transmit an infectious agent between people)–in her case, a beloved wooden doll clothed in Baratheon House colors from when she was an infant. Her father, Stannis, implies that this may have been a form of bioterrorism–that Stannis received the doll from a Dornish trader on Dragonstone. He tells his daughter, “No doubt he’d heard of your birth, and assumed new fathers were easy targets” (S05E04). “I still remember how you smiled when I placed that doll in your cradle, and you pressed it to your cheek,” where evidence of greyscale is still present (4).

Shireen Baratheon with facial greyscale.

Treatment

A number of remedies have been proposed to treat greyscale, but none of them are proven effective. They include treating it with boiling water containing limes; chopping off of the infected limbs; religious means/magic; and maybe fire–in A Dance with Dragons, Tyrion touches a Stone Man with his torch, and the Stone Man shrieks in pain (even while having bone showing through his skin, which apparently doesn’t bother him).  Whether fire could be a cure is unclear.

Also in A Dance with Dragons, we read of Tyrion’s musings on treating greyscale: “He had heard it said that there were three good cures for greyscale: axe and sword and cleaver. Hacking off afflicted parts did sometimes stop the spread of the disease, Tyrion knew, but not always. Many a man had sacrificed one arm or foot, only to find the other going grey. Once that happened, hope was gone.” As such, the infectious agent seems to enter into the bloodstream and spread throughout the body at some point during the infection, and at this point, local measures such as amputation are no longer useful. Other home remedies, such as cleansing the infected area with vinegar, are also employed. In fact, Jon Connington, once he realizes he’s been infected, soaks his hand in bad wine instead of vinegar, because he believes that if he asks for vinegar, it will be an obvious “tell” that he has the disease.

In the TV series (S05E04), Stannis says to Shireen regarding her infection, “I called in every Maester in this side of the world, every healer, every apothecary. They stopped the disease and saved your life.” However, no details are given on the show regarding how it was stopped (medicine? magic?), or if a mechanism exists that could be used on an adult instead of an infant. When Daenerys asks Jorah if there is a cure, he tells her simply that he doesn’t know, and she directs him to leave, find one, and return to her.

Cultural response

Largely, those with greyscale are shunned and sent elsewhere, especially to the ruins of Valyria (5) where a whole colony of Stone Men live. Shireen asks Stannis, “Are you ashamed of me, Father?”, understanding that her obvious greyscale scars are a sign of stigma for their entire family. Stannis tells his daughter, “Everyone advised me to send you to the ruins of Valyria to live our your short life with the Stone Men before the sickness spread throughout the castle. I told them all to go to hell.” (Father of the Year before that whole burning stuff, Stannis!)

Similarly, both the books and show note the existence of greyscale beyond the wall among the Wildlings–and that the free folks’ response to greyscale infection is exile and/or death. In the books, a wildling named Val sees Shireen, and notes Shireen has a condition they call “the grey death,” which is always fatal in children–because they’re given either hemlock, a pillow, or a blade rather than be allowed to live. She also suggests that greyscale may become quiescent and return later, saying “The grey death sleeps, only to wake again. The child [Shireen] is not clean.”

On the TV version, the wildling Gilly takes the place of Val, and while she is not as frightened of Shireen’s greyscale, she notes she’s also had experience with the illness.  She tells the tale of two of her sisters, who contracted greyscale (exactly how, we’re not told). Though he did not kill them as Val suggested, Gilly noted that her father “made them move out of the keep, into the hut outside. None of them were allowed to go near them, but we heard them, especially at night. They started to sound not like themselves.” Gilly saw them again “only once, at the end. They were covered with it. Their faces, their arms. They acted like animals. My father had to drag them out to the woods on a rope.” Shireen doesn’t find out what happened to them after that, but we can guess it’s not good.

Gilly and Shireen at Castle Black.

What are some real-life parallels?

Clearly greyscale is another invention of Martin’s that doesn’t quite match up to any real infectious disease (6), and I’ll leave that linked article to summarize some of the pros and cons of the alternative diagnoses. But given the other historical parallels, leprosy (Hansen’s disease) is probably the closest real-life affliction to greyscale, due to the route of transmission (I’ll elaborate on that below), symptoms, incubation period, and particularly the cultural response to those who are affected.

Like those with leprosy, sufferers of greyscale can become disfigured, are considered “unclean” and shuffled off to the far corners of the map, feared and then ignored by their family and friends. Connington, when hiding his infection, noted that “Queer as it seemed, men who would cheerfully face battle and risk death to rescue a companion would abandon that same companion in a heartbeat if he were known to have greyscale”–a similar phenomenon to what still can happen today with stigmatized diseases such as leprosy. A case of greyscale is a source of stigma for both the sufferer (even if they survive, like Shireen) and for the family, as there will always be those who fear contagion.

Though evidence is gathering that leprosy is actually transmitted via the respiratory route (like its cousin, tuberculosis), for centuries people believed it could be spread by touch, as greyscale is. So even though the transmission route for the two diseases really isn’t the same, the *presumption* that leprosy can be spread by touch is still incredibly common. The lengthy period between infection and outward symptoms of the affliction is also similar, taking years from exposure to the final stages of infection that we see in the Stone Men. Leprosy can also take years or decades to progress, and while untreated leprosy is not typically a cause of death itself, it can lead to death indirectly due to secondary infections and other issues.

One of the early signs of leprosy is also numbness in an affected area as nerves are damaged by the infection, as Tyrion tried to evaluate after his exposure to the Stone Men, as well as a general thickening and stiffness of the skin. It doesn’t get to the level that’s seen with the Stone Men–one of the biggest problems with leprosy is actually secondary infections, which can lead to loss of digits or even whole limbs rather than a whole-body calcification of the skin–but many of the hallmarks of greyscale are very similar to leprosy.

While leprosy is now treatable with antibiotics, it wasn’t all that long ago that we had our own leper colonies in the U.S. (you can read about one of them here, also on a near-deserted island where the afflicted were largely left to fend for themselves with some occasional governmental assistance, similar to Valyria/the Sorrows). Martin himself even notes that Valyria is “like a leper colony.” Leprosy, and its stigma, remains an issue in some countries still today, and the purposeful isolation of those who have leprosy and exclusion from society persists.

Image of the U.S. leper colony at Molokai, Hawaii, circa 1900.

However, while there are many similarities, leprosy doesn’t have an epidemic form equivalent to the grey plague. Described in A Dance with Dragons, it’s suggested that the grey plague wiped out half of Oldtown in the southwest of Westeros, and was only stopped by closing the gates and preventing anyone from entering or leaving. And like the Black Plague, the grey plague’s arrival in Pentos (a city in Essos) came by ship, and its spread into the city was possibly aided by rats. So is there an airborne form of greyscale that causes the grey plague? Could it be similar to Yersinia pestis, the bacterium that causes the Black Plague: transmitted by rats and fleas (or skin to skin in the case of greyscale) in its more mild form, but occasionally ending up in the lungs of an unfortunate victim and spread via the air after that, causing massive epidemics? Is it zoonotic, spread via rats? Will we see the grey plague on the TV series or not?

Lingering Questions

While comparisons to other real infections are interesting, my real question is–what is Martin going to do with greyscale? How does it feature into the larger end game, when we move beyond just a human “Game of Thrones” into the battle for humanity itself against the White Walkers and their army of undead wights? With all the time spent on the affliction in both the books and particularly in the show, there has to be some payoff somewhere, right?

In some ways, the wights beyond the wall and Stone Men are similar–undead, or nearly-dead, aggressive hunters of humans, with no sense of humanity left. When we last saw Jorah in the TV version, he had confessed his affliction to Daenerys, and she sent him off to find a cure. Will he find Dany after her arrival in Westeros and bring with him an army of (now healthy?) Stone Men–healed by fire perhaps, to fight against those brought back to life by ice? Will he return to Valyria–an area largely abandoned except as a place of exile for the Stone Men since The Doom a thousand years ago–and learn the truth of what happened there? Could Valyria provide a key to ending both greyscale and perhaps also the White Walkers? Or is the haunting poem Tyrion and Jorah recited as they rowed down the Rhoyne toward the ruins of the city foreshadowing what’s going to happen to Westeros?

It’s interesting that most stories open with an infection that ushers in the apocalypse: The Stand; The Passage series; The Walking Dead; World War Z; I Am Legend; the MaddAddam trilogy; the Planet of the Apes reboot; The Last of Us video game; even back a century or two to the Scarlet Plague or The Last Man. I could go on and on. Martin is known for taking many fantasy tropes and turning them on their heads, so instead of having a plague begin the downfall of society, could greyscale serve to save it somehow? With reportedly two seasons left in the TV series after Sunday’s Season 6 finale, we’ll have less time to wait and find out than it takes a newly-infected greyscale patient to turn into a Stone Man.

Notes

(1) The information provided on greyscale in this article is a mix of literature from the books and the show. Note that the show, to my recollection, hasn’t delved into the grey plague, so information on that malady comes exclusively from the books. Also note some of the victims of greyscale differ in the books versus in the show (eg Jorah Mormont taking Jon Connington’s place in the TV version).

(2) Though Jorah denies any contact with the Stone Men initially, and it isn’t 100% clear if he was touched during the scene, he does back off from Daenerys when she moves toward him in S06E05, when he discloses his condition (which is now all the way up his forearm). This suggests he does believe he acquired it through direct contact with a Stone Man.

(3) Though these sufferers are uniformly called Stone Men, and the ones seen on-screen appear to be male, presumably there are also Stone Women. Possibly loss of hair as the skin calcifies could lead to a more androgynous look.

(4) I should note there are some alternative views about exactly how Shireen’s greyscale infection was acquired, and about the use of greyscale as a biological weapon.

(5) Or on “the Sorrows” in the novels.

(6) I don’t agree with several things in that article, written by a dermatologist. It concludes based mainly on symptoms and a bit on epidemiology that greyscale is something more like smallpox or HPV and largely rules out a leprosy-like illness. It also notes the potential for an infectious agent that’s only infectious to those with an underlying genetic susceptibility, but I don’t think there’s much evidence to suggest that.

Find other posts in today’s carnival on the science of Game of Thrones!

One Reason Scientists and Science Writers Want to Talk About Game of Thrones by Matt Shipman

Biology Would Leave the Game of Thrones Dragons Grounded by David Hone

Dire Wolves Were Real by Brian Switek

Winter is coming: climate change and biodiversity beyond the Wall by Jacquelyn Gill

White Walkers: a warning letter from north of The Wall by Michelle LaRue

Tales from a Westeros Geologist by Miles Traer

A Storm of Chemistry by Raychelle Burks

The Heating Engineers of Winterfell by Jesse Emspak

Plague in Victorian San Francisco–lessons for public health communication

I have a post up today at the Scientific American Guest blog, discussing how an earthquake and denial led to prairie dog plague. It details an outbreak of plague in Victorian San Francisco–the first time plague hit the United States–and the many downstream consequences of that outbreak (which began in 1900 and wasn’t really contained until 1908). While the story is over at SciAm, here I wanted to talk more about why the outbreak became such a public health disaster.

The outbreak was first recognized by Dr. Joseph Kinyoun, a bacteriologist who had been, until his transfer to San Francisco, heading up the United States Hygienic Lab, the precursor to the National Institutes of Health. Charged with inspecting incoming ships, Kinyoun had the power to quarantine ships and their crew in harbor, in an effort to keep plague out (which was already circulating in port cities of Honolulu, Sydney, and Tokyo, amongst others). When Kinyoun first suspected a case of plague, San Francisco merchants quickly banded together to deny any such pestilence in their city. What followed was a mess of ineffective quarantines, fights over scientific data, accusations of “spiking” corpses with plague samples Kinyoun had brought with him from Washington, D.C., and an eventual call for Kinyoun’s execution.

History shows that Kinyoun was right–San Francisco had plague cases, and the plague would continue to smolder for almost a decade. As I note in the post, it still lingers today in squirrels and rodents from the Pacific Ocean inland to the Great Plains. So what went wrong, if Kinyoun clearly had the facts on his side?

Like many scientific issues today, it wasn’t the facts that ended Kinyoun’s career in San Francisco, but his messaging. Admittedly, he was acting without all the knowledge of plague transmission that we have today–it wasn’t confirmed in 1900 that rat fleas were the main vector of the disease from rodents to person, and so Kinyoun couldn’t have been sure his attempts to quarantine Chinatown would be ineffective. Furthermore, in some cases, he was merely obeying orders from his superiors. His boss, Surgeon General Walter Wyman, had recently published a monograph on plague, endorsing the idea that plague selectively targeted Asians due to their particular diets and their poverty.

Still, the way Kinyoun went about attacking those most affected in the initial outbreak–the Chinese immigrants–only served to terrify them and drive plague cases underground. Indeed, when public health officers went door-to-door searching for plague cases, one anecdote notes that a game of dominoes was set up in a home, and all the men stayed perfectly still with dominoes in their hands while officers searched the home for anyone with plague symptoms. Little did they know that a plague corpse was sitting at the card table, “Weekend at Bernie’s” style (1). Other Chinese fled Chinatown, bunking with friends and relatives elsewhere when possible. Threats were made to burn Chinatown (as had recently happened in Honolulu); Kinyoun tried to bar travel by any “Asiatics” on trains or boats leaving the city, clearly a race-based order. Furthermore, even when cases of plague were identified in Chinatown, the very practice of carrying out autopsies was offensive to the Chinese, giving them even more reason to hide their sick and dead rather than cooperate with Kinyoun and other public health authorities.

Kinyoun left the city in 1901, and eventually Rupert Blue was brought in to control the outbreak. Taking lessons from those who’d been there prior (and were unsuccessful), Blue took a much more diplomatic tack. He secured the assistance of a Chinese translator, Wong Chung, and worked within the Chinese community to gain their support. He often downplayed the outbreak–never suggesting it wasn’t happening or wasn’t important, but trying to differentiate hype from supported fact. He worked to clean up Chinatown, both in its housing and in rat infestations, rather than to quarantine infected areas. He noted that plague could occur in many different races, and avoided scapegoating one particular ethnic class. He also reached out to businessmen to educate them, and show how important cleaning up the city was for their bottom lines. He worked with the facts as Kinyoun did, but he recognized the importance of grassroots support in his campaign, and targeted reasons why various factions should support his various anti-plague measures.

In the end, while Kinyoun was practically run out of town on a rail, Blue was given banquets and numerous accolades. He served as the Surgeon General from 1912-1920, and his methods for cleaning up the city led to a decrease not only in plague, but in many infectious diseases. While Kinyoun’s science was sound, Blue managed to break down barriers and work with those who could help him spread his message, and take ownership of the work that needed to be done. He framed* the threat in terms that meant something to the populations he was working with: businessmen and threat to their incomes; immigrants’ threat to health, with promises to respect their culture and help them make their homes cleaner places to live; city and state government, noting the threat to the very reputation of California and San Francisco in the US and around the world. His tactics served him well in 1902-08, and should serve as a reminder to science communicators today as well.

(*I know that term is somewhat tainted in some circles, but bear with me…)

Further reading and references

Chase, “The Barbary Plague”.

Echenberg, “Plague Ports: The Global Urban Impact of Bubonic Plague, 1894-1901.”