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

Why I vaccinate my kids

Being a new parent is exhausting. All of a sudden, you’re out of the hospital and on your own with this amazing, tiny human, and you alone are responsible for her care. You’re given reams of paperwork about feeding and sleeping, developmental milestones, red flags to look out for. You’re inundated with information you barely have time to look at. Mom is trying to heal from childbirth while barely sleeping, while her partner is trying to pick up the slack and pitch in as much as possible. You both fumble with the car seat, thinking that NASA must have equipment that’s easier to figure out. You obsessively check your sleeping baby to make sure she’s still breathing. You worry about every sneeze and try to decipher her cries. Is the diaper too tight? Is this acne normal? What do I do about her poor dandruffy head?

Do I vaccinate?

vaccineWilliam receiving the first of  his 2-month vaccinations

I know it can be scary. You might have heard from friends or relatives, or read on the internet, that vaccines can harm your baby. You may be concerned about autism, or think that “natural immunity” is better than that which develops from injections. You may think that the diseases she’s being vaccinated against “aren’t all that bad,” or that kids today receive too many vaccines. You might feel that your physician is “bought out” by “big Pharma” and that your health care providers are writing off your concerns.

I know you just want to do what’s best for your child. I feel you. I’m the parent of a teenager, a tween, and a 2-month old. Here is why I vaccinate my children.

William vax 2William receiving his vaccinations

I’ve spent almost 20 years of my life studying infectious diseases up-close and personal, not from random websites on Google. I’ve worked with viruses and bacteria in the lab. I respect what germs are capable of. I worry about vaccine-preventable diseases coming back because of low levels of herd immunity. I cry over stories of babies lost to pertussis and other vaccine-preventable diseases. As I’ve noted before, chicken pox has played a role in the deaths of two family members, so I don’t view that as just a “harmless childhood disease.” Vaccines have eradicated or severely reduced many of the deadliest diseases from the past: smallpox, polio, measles, diptheria.

But that’s not the only reason I vaccinate. I vaccinate because I’m all too aware of the nasty diseases out there that still don’t have an effective vaccine. My current work focuses on a germ called methicillin-resistant Staphylococcus aureus (“MRSA”), a “superbug” which kills about 11,000 people every year in the United States. We have no vaccine. I previously worked on two different types of Streptococcus: group A and group B. Group B is mainly a problem for babies, and kills about 2,000 of them every year. It leaves many others with permanent brain damage after infection. We have no vaccine. Group A kills about 1,500 people each year in the U.S. and can cause nasty (and deadly) infections like necrotizing fasciitis (the “flesh-eating disease”). We  have no vaccine. These are all despite the fact that we still have antibiotics to treat most of these infections (though untreatable infections are increasing). Infectious diseases still injure and kill, despite our nutritional status, despite appropriate vitamin D levels, despite sanitation improvements, despite breastfeeding, despite handwashing, despite everything we do to keep our kids healthy. This is why protection via vaccination is so important for the diseases where it’s available. If vaccines were available for the diseases I listed above, I’d have my kids get them in a heartbeat.

w after vax 1William with daddy, right after finishing his vaccinations

I’ve done my best to keep my kids healthy and safe. I nag about bicycle helmets and make sure they’re getting exercise. I make them eat vegetables. I don’t move the car until everyone is buckled up. My older kids were in booster seats for what felt like forever, as both were on the small size for their age. Vaccinations are just one more part of this arsenal. I’m well versed in the safety data and know that most vaccine side effects are minimal (fever, soreness at injection site). They don’t cause autism, or SIDS, or any of the other claims made by dubious sites such as Natural News or Mercola. They do save lives and prevent disease by training the body to recognize and fight germs.

My youngest recently went in for his 2-month shots. He cried a bit when he received them, but not any worse than he does when he needs to be burped, changed, or held. He slept a little extra that evening, but was back on his normal schedule the next day. At his visit, he received the oral rotavirus vaccine; his second Hepatitis B shot; his pneumococcal vaccination; and the combination shot including diptheria, pertussis, tetanus, polio, and Haemophilus influenzae (DTaP/polio/Hib). Each one I see as a small measure to support his health and safety, as well as my own peace of mind, knowing that I did what I could to protect him from infections that used to kill thousands of children every year. Some still do when vaccination isn’t available or accepted–measles killed over 120,000 people in 2012, most of them young children who hadn’t been vaccinated.

W after vax 3William at home after his vaccinations

We all try to do the best by our children. As a scientist who’s studied infectious diseases, vaccination is a no-brainer for me, and I worry for the children out there who are left undefended against these infections because of misinformation and wrongly-placed fears. I know these parents are trying to do right by their kids, but infectious diseases don’t recognize good intentions. As I sit here with my baby breathing softly beside me, I am thankful for those who came before me and dedicated their lives to protecting children like him, and grateful that he will never have to suffer from infections that were the scourge of earlier generations.

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Student guest post: The Fallacious Fad of Foregoing Vaccinations

It’s time for this year’s second installment of student guest posts for my class on infectious causes of chronic disease. First one this year is by Dana Lowry.

Humans have a long history of illness and death from infectious diseases. It wasn’t until the 1790s that we had a solution. Edward Jenner recognized that milkmaids never contracted smallpox but suffered from a more mild disease, cowpox. Jenner took pus from a cowpox lesion on a milkmaid’s hand and placed it in an incision he made in an eight year-old boy’s arm. He then exposed the boy to smallpox; the boy didn’t contract the disease, proving he was immune. Jenner experimented on several other children, including his own 11-month old son, and his theory of passing on immunity proved to be successful. The Latin term for cow is vacca, which is where Jenner coined the term “vaccine”. Jenner’s discovery eventually led to the eradication of smallpox from the U.S. in 1949 and from the world in 1979. For over a century, vaccines were limited to preventing smallpox but as we know today, vaccines prevent a large number of diseases.

Although many developing countries still suffer from the burden of preventable infectious diseases, the U.S. has greatly increased the life expectancy and quality of life through the use of vaccines. In the 1940s, the U.S. recommended vaccines for diphtheria, pertussis and tetanus; polio was added in the 1950s. In the 1970s, measles, mumps and rubella (MMR) were added to list. Today in the U.S., immunizations are recommended for 17 vaccine-preventable diseases during one’s lifetime and more are available for individuals traveling outside of the U.S. Many of these vaccinations are combined so they can prevent multiple diseases from one series of immunizations. The increase in life expectancy in the 20th century is largely attributable to vaccines. For each birth cohort vaccinated, 33,000 lives are saved, 14 million cases of disease are prevented, healthcare costs are reduced by $9.9 billion and $33.4 billion is saved in indirect costs. The Bill Gates Foundation believes that vaccines are one of the most cost-effective investments in global health, saving about 2.5 million lives each year. One child dies every 20 seconds from vaccine-preventable diseases while tens of thousands of other children suffer from severe illnesses and permanently disabling diseases.

Despite the facts, less and less parents are choosing to vaccinate their children today because of fears that vaccines are unsafe. Much of the controversy started with Dr. Andrew Wakefield, a former British surgeon and medical researcher. Wakefield published a paper in 1998 linking the MMR vaccine to autism and bowel disease. Wakefield’s entire study was found to be fraudulent and the infamous paper was retracted in 2010. But, what got more attention than a retracted science paper was Jenny McCarthy sharing her personal life story of how her son got autism from a vaccine on the Oprah Show. Unfortunately, more moms keep up-to-date with Oprah and popular news rather than science and still do not know the truth behind Wakefield’s falsified study; therefore, the autism myth continues.

Furthermore, parents argue “herd immunity”. If your children are effectively vaccinated then why would I have to worry about mine? First, many vaccine-preventable diseases still exist in other countries and can easily be brought into our country; second, some individuals do not build immunity to the disease even after vaccination. The more and more parents that opt out of vaccinations, the less protection their children have from the rest of the “herd”. Additionally, parents argue that their children should contract diseases “naturally” through the environment to build immunity. Parents don’t fully understand the severity of these diseases because many have been virtually eradicated through the successful use of vaccines. Though some crippling effects of polio still linger, it is rare to come across someone wearing braces or using a wheelchair as a result of a polio infection in the U.S. Many vaccine-preventable diseases can cause death during the initial acute illness and if the individual survives, he or she may be left with chronic effects that last a lifetime. Polio can lead to temporary or permanent paralysis, deformities in the hips, ankles and feet; measles, mumps and varicella can all lead to brain damage and mumps is known to cause deafness; hepatitis B can cause permanent liver damage and even liver cancer. The list of damaging effects goes on and on.

In some areas throughout the U.S., as many as 1 in 20 kindergarteners have not been vaccinated. As the antivaccination fad grows in American so do the infectious disease rates. Measles was said to be eliminated from the U.S. in 2000 but an average of about 60 cases of measles occurs each year, typically from traveling. However, in 2011, there were 17 measles outbreaks in U.S. communities and the number of cases jumped to 222. In 2012, the U.S. had one of the largest pertussis outbreaks in nearly 50 years. Nationwide, over 85,000 vaccine-preventable diseases occur each year. I am not arguing that vaccines have no potential side effects and have never caused adverse effects or even death in children. However, I do think vaccines have done considerably more good than harm. So I urge parents, before deciding to withhold your children from vaccinations, look into the facts and make a decision based on science – not popular news. Although outbreaks of disease have been conquered in the past, many vaccine-preventable diseases remain throughout the world and the U.S. is not immune to future outbreaks.

 

“Pox” by Michael Willrich

Next to Ebola, my favorite virus would probably be smallpox (Variola virus). I mean, now that it’s eradicated in nature, what’s not to love about the mysteries it’s left us–where it came from, why it was so deadly (or, not so deadly, as in the emergence of the “mild” form, variola minor), and will a new poxvirus emerge to take its place? The topic is particularly germane since the debate still rages on about the fate of the world’s smallpox stocks. Smallpox has killed untold millions and influenced the destiny of societies; and as Michael Willrich details in his new book, Pox: An American History, the legacy smallpox has left us is still alive and well today.
Continue reading ““Pox” by Michael Willrich”

New site–“History of Vaccines”

This is great. The College of Physicians of Philadelphia has launched a site on The History of Vaccines. I’ve been poking around, and there’s an incredible amount of stuff to check out. They have a nice FAQ, Top 20 questions about vaccination, as well as some great activities (herd immunity! learn about Koch’s postulates! understand the relative risk of vaccination versus other events!) and a metric fuckton of articles and images. Looks to be a fantastic resource for students, and for anyone interested in understanding vaccination.