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What separates George RR Martin’s fictional universe from so many others in fantasy is his consideration of all aspects of life in Westeros and Essos. Swords, arrows, poison, white walkers, and dragonfire aren’t the only threat to the inhabitants of Martin’s world; myriad illnesses have plagued the Seven Kingdoms over the years. While the afflictions in A Song of Ice and Fire are fictional, Martin draws on real life maladies as inspiration. Given my background in medicine, I thought it would be fun to try and pinpoint which real world diseases Martin used as inspiration for all the pestilence in his fictional world.

Greyscale — The most discussed affliction in A Song of Ice and Fire and the only one to get significant screen time of Game of Thrones, Greyscale is an amalgamation of multiple diseases. Greyscale seems to be transmitted by close contact with those who are already infected and predominates in the cold damp climates such as Dragonstone and the Iron Islands.

The symptoms of greyscale begin with numbness of the extremities which progresses distally to proximally. Those with possible exposure can check for the infection by pricking their toes and fingers to check for loss of sensation. The skin of the affected limbs turns grey and hard, resembling stone. Eventually blindness can occur as greyscale progresses to the trunk and face.

All of these symptoms are clearly inspired by leprosy, an illness caused by Mycobacterium Leprae which characteristically involves the skin and peripheral nerves. More advanced cases can lead to destruction of the nasal cartilage and blindness.

However, the late-stage symptoms of greyscale differ from those of leprosy (which while disabling, is rarely fatal). As greyscale progresses, those infected eventually develop madness and become aggressive before ultimately succumbing to the disease, which is more characteristic of rabies. And the amped up infectivity of greyscale more closely resembles smallpox.

The Shivers — The long reign of King Jaehaeys and Queen Aylsanne Targaryen was perhaps the most peaceful and prosperous in the history of the Seven Kingdoms, yet it was nonetheless marred by several tragedies. Chief among these was the Westerosi pandemic known simply as “The Shivers.” The diseased claimed the lives of thousands including the young princess Daenerys, whose death threw into doubt the doctrine of Targaryen Exceptionalism.

The disease began with body chills that were unable to be stayed by blankets or warm soup. Shivering would follow, which rapidly progressed from slight shaking to full blown rigors. Once the victim’s lips turned blue and he or she began coughing up blood, death soon followed — usually only a matter of days after the symptomatic onset. Only one out of every five who became symptomatic recovered, with the Stranger coming for the rest. Multiple remedies were attempted by maesters across the Seven Kingdoms. All proved ineffective.

The Shivers swept across the Seven Kingdoms but port cities, including King’s Landing, were hit hardest. Among the suspected causes of the illness were the small black rats seen in shipyards — which while never definitively confirmed by maesters, households across the Seven Kingdoms suddenly were willing to pay a premium for a feline companion.

The Shivers seems plainly influenced by the infection caused by Yersinia Pestis — better known as the plague. Specifically, the Shivers most resembles the pneumonic form of the disease which is characterized by rapid onset of chills and fever which is accompanied by hemoptysis (coughing up blood) and carries a near 100% mortality when left untreated. Plague was responsible for the infamous Black Death of the middle ages and was transmitted by fleas which infested the black rats harbored on merchant vessels (though the disease can also be passed from infected human host to infected human host).

Winter Fever — Just as the brutal Targaryen civil war known as the Dance of Dragons was coming to to a merciful end, Westeros was struck by another pandemic. The Winter Fever — which as you might expect occurred during a long six year winter — swept across Westeros and decimated a large portion of the population of King’s Landing.

While perhaps just a shade less deadly than the Shivers, the Winter Fever was still remarkably virulent. Symptoms began with facial flushing, quickly followed by rising fever and rigors. Bloody sweats and delirium developed on the third day and by day four 75% of the victims were dead, with the remaining 25% on the road to recovery as their fevers broke.

Martin is most likely drawing on the influenza virus as inspiration for Winter Fever, specifically the Spanish Flu pandemic of the early 20th century. Caused by the H1N1 strain of influenza (the same strand that caused the “swine flu” outbreak earlier this decade), the Spanish Flu infected approximately 500 million people worldwide between 1918 and 1920, resulting in the death of 3–5% of the world’s population.

The high spiking fevers are characteristic of influenza, as is the tendency to occur in the winter months when people are more closely clustered together indoors. Delirium can be observed in severe cases of influenza, though the symptom bloody sweats is likely Martin borrowing from hemorrhagic fevers such as Dengue.

Bloody Flux — The Bloody Flux is well known both in Westeros and Essos and has plagued the armies of these nations since the Dawn Age. While cut from the show, the Bloody Flux is one of the many headaches Daenerys is forced to confront during her rule of Meereen. The disease spreads across Slaver’s Bay from Astapor to Yunkai, leading the Mother of Dragons to bar the doors of Meereen to refugees.

As you perhaps can infer, the Bloody Flux is characterized by fevers and bloody diarrhea. Prevention via quarantine is key, as there is no known treatment and the disease carries a nearly 75% mortality rate.

Again, Martin’s inspiration is rather obvious — the Bloody Flux is certainly drawing from hemorrhagic dysenteries caused by the Shigella and enterohemorrhagic Escherichia Coli bacteria (E.Coli). Both are spread by fecal-oral transmission, usually by drinking water or consuming food that has been contaminated by an infected individual. While sanitation and antibiotics have significantly curbed the impact of these illnesses in developed nations, dysentery remains a major health issue in the developing world.

Firewyrm Infection — Both in the sense of my medical background and familiarity with Martin’s work, it takes a lot to truly shock me or turn my stomach. Yet reading about the fate that befell young Aerea Targaryen did just that.

The niece of King Jaeherys, Aerea was stubborn, bold, and firey. At 12 years old, following an argument with her mother, Aerea mounted Balerion the Black Dread — the very same dragon ridden by Aegon the Conquerer — and disappeared. Aerea and Balerion’s whereabouts were unknown until, over a year later, Balerion carried the princess back to King’s Landing — emaciated and dying.

From Fire and Blood, Artist Doug Wheatley

In the histories of Westeros, Aerea is simply stated to have died of fever. However the account of Septon Barth reveals a much more harrowing fate. The princess’s skin was burning hot and covered in boils. Movement was seen below her skin as if living things moved inside her. As she began “cooking from inside” and smoke issued from various orifices the septon and grand maester lowed her into a tub filled with ice. Her heart immediately stopped, but much worse writhing snake-like creatures immediately crawled out from her skin and then perished in the cold ice.

Something so horrible seems on the surface to be purely the fantastical product of Martin’s occasionally twisted imagination. And to be sure, the creatures infesting poor Aerea Targaryen are heavily implied to be spawn of the firewyrms that lived in Valyria. As the only Targaryen dragon to have been born in Valyria before the doom, Balerion likely carried the princess to his birthplace and both were seemingly attacked by firewyrms which inhabit the doom.

Yet, the fate of Aerea may not be purely an invention of fantasy. Numerous parasitic infections exist in the developing world of which the majority of us are blissfully ignorant. One of these, the Guinea Worm might just have provided inspiration for the firewyrm infection described by septon Barth. Caused by the parasite Dracunculus medinensis, individuals become infested by drinking contaminated water. Approximately one year later, the infected individual develops fever and a painful enlarging blister, usually on the lower extremity. When the blister is submerged under cold water, the worm bursts from the blister and releases thousands of larvae into the water.

Perhaps White Walkers aren’t the most terrifying thing in Westeros after all.

Articles on Medscape, Wikipedia, and A Wiki of Ice and Fire were used as references in writing this column.