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REVIEW
History of the Plague: An Ancient Pandemic for the
Age of COVID-19
Kathryn A. Glatter, MD, Paul Finkelman, PhD
Gratz College, Melrose Park, Pennsylvania.
ABSTRACT
During the fourteenth century, the bubonic plague or Black Death killed more than one third of Europe or
25 million people. Those afflicted died quickly and horribly from an unseen menace, spiking high fevers
with suppurative buboes (swellings). Its causative agent is Yersinia pestis, creating recurrent plague cycles
from the Bronze Age into modern-day California and Mongolia. Plague remains endemic in Madagascar,
Congo, and Peru. This history of medicine review highlights plague events across the centuries. Transmis-
sion is by fleas carried on rats, although new theories include via human body lice and infected grain. We
discuss symptomatology and treatment options. Pneumonic plague can be weaponized for bioterrorism,
highlighting the importance of understanding its clinical syndromes. Carriers of recessive familial Medi-
terranean fever (FMF) mutations have natural immunity against Y. pestis. During the Black Death, Jews
were blamed for the bubonic plague, perhaps because Jews carried FMF mutations and died at lower
plague rates than Christians. Blaming minorities for epidemics echoes across history into our current coro-
navirus pandemic and provides insightful lessons for managing and improving its outcomes.
Ó 2020 Elsevier Inc. All rights reserved. The American Journal of Medicine (2021) 134:176−181
KEYWORDS: Bioterrorism; Black Death; Bubonic plague; COVID-19; Evolutionary adaptation; Familial Mediterra-
nean fever (FMF); Pneumonic plague; Pyrin; Yersinia pestis
INTRODUCTION This history of medicine article sheds light onto the plague
Killing more than 25 million people or at least one third of and provides insights that can help us manage the COVID-
Europe’s population during the fourteenth century, the 19 epidemic.
Black Death or bubonic plague was one of mankind’s worst
pandemics, invoking direct comparisons to our current HISTORY OF PLAGUE EPIDEMICS
coronavirus “modern plague.”1-3 An ancient disease, its The plague has afflicted humanity for thousands of years.1-3
bacterial agent (Yersinia pestis) still causes periodic out- Molecular studies identified the presence of the Y. pestis
breaks and remains endemic in some parts of the world.4-6 plague DNA genome in 2 Bronze Age skeletons dated at
Additionally, because it could be weaponized for world bio- roughly 3800 years old.9 In the biblical book 1 Samuel
terrorism, understanding its clinical syndromes, epidemiol- from approximately 1000 BCE, the Philistines experience
ogy, and treatment options remains critical for medical an outbreak of tumors associated with rodents, which might
practitioners.5,6 Finally, recent molecular discoveries link- have been bubonic plague.3 Scholars identify 3 plague pan-
ing recessive familial Mediterranean fever mutations to demics.10,11 The first pandemic or Justinian plague proba-
plague immunity have revolutionized how scientists and bly came from India and reached Constantinople in 541-
historians alike view this novel evolutionary adaptation.7,8 542 CE. At least 18 waves of plague spread across the Med-
iterranean basin into distant areas like Persia and Ireland
Funding: None. from 541 to 750 CE.10,11
Conflicts of Interest: None. The second pandemic or Black Death arrived in Messina
Authorship: Both authors had access to the data and a role in writing in Sicily, probably from Central Asia via Genoese ships car-
this manuscript.
Requests for reprints should be addressed to Kathy A. Glatter, MD,
rying flea-laden rats in October 1347, which initiated a
Gratz College, 7605 Old York Road, Melrose Park, PA 19027. wave of plague infections that rapidly spread across most of
E-mail address: [email protected] Europe like a relentless wildfire.10-12 In Europe, plague-
0002-9343/© 2020 Elsevier Inc. All rights reserved.
https://doi.org/10.1016/j.amjmed.2020.08.019
Glatter and Finkelman History of the Plague 177
stricken citizens were often dead within a week of contracting estimated that more than 200 million people have died from
the illness. Ultimately, at least one third of the European pop- the plague throughout human history.10
ulation (more than 25 million people) died between 1347 and
1352 from the Black Death.10-12 The plague spread to France PLAGUE MICROBIOLOGY
and Spain in 1348 and then to Germany, Switzerland, and Y. pestis is an aerobic, gram-negative coccobacillus in the
Austria. It decimated London in 1349 and reached Scandina-
family Enterobacteriaceae.21-23 Genetic DNA analysis
via and northern England by 1350.10-12 The plague died out
shows that it diverged from its
by the century’s end, but outbreaks
enteric pathogenic relative, Yersinia
resurfaced and spread throughout CLINICAL SIGNIFICANCE
pseudotuberculosis, up to 6000 years
Europe over the next 400 years. In 24
1656-1657, two thirds of the popula- The Black Death or bubonic plague ago. After incubation for 24 to
48 hours in blood or on MacConkey
tion in Naples and Genoa died from killed more than 25 million people in agar at 37˚C, small bacterial colo-
the disease. In 1665-1666, London fourteenth-century Europe. nies can be identified.21-23 Its pri-
lost about one quarter of its citizens Yersinia pestis (the plague bacteria) mary vector for transmission is the
to plague, about 100,000, and the can be easily weaponized as a bioter- Xenopsylla cheopis flea, although
same number died in Vienna in rorism agent. roughly 80 species of fleas can carry
1679.3, 13, 14 Moscow recorded more Early plague treatment is curative, but it. During the Black Death, the flea
than 100,000 plague deaths during
its symptomatology can be nonspe- was transported by the black rat or
1770-1771.3,13,14 21-23
The fourteenth-century bubonic cific. Modern outbreaks still regularly Rattus. A controversial new
occur. The plague existed in the theory argues that ectoparasites
plague transformed European soci- such as human fleas and lice also
ety and economies, leading to ancient world and has killed more than
spread the disease during the second
severe labor shortages in farming 200 million across centuries. 25
and skilled crafts.1-3 The geopoliti- Familial Mediterranean fever carriers plague pandemic. Fleas can also
survive in infected clothing or
cal impact included a decline in have plague immunity, which is an grain.11,19-21 The bacteria multiply
power and international status of the important evolutionary adaptation. in infected rodents (more than 280
Italian states.15 During the Black
mammalian species can serve as
Death, European Christians blamed
carriers) and block the fleas’ ali-
their Jewish neighbors for the plague, claiming Jews were mentary canal, causing the fleas to regurgitate the Y. pestis
poisoning the wells. These beliefs led to massacres and vio-
bacteria into its animal host.11,19-21 The bacterium is named
lence.2,16 At least 235 Jewish communities experienced
for the Pasteur Institute physician Alexandre Yersin, who
mass persecution and destruction during this period, often
provided the first, most accurate description of its causative
preemptively in a futile effort at plague containment.16 The
agent in 1894 during the Hong Kong outbreak. However,
ancient physicians Hippocrates (c. 460-c. 370 BCE) and
the Japanese physician Shibasaburo Kitasato was an inde-
Galen (129-c. 210 CE) promoted the miasma theory, or poi-
pendent coinvestigator whose bacterial plates were unfortu-
soned air, to explain disease transmission, which Medieval
nately contaminated and led to erroneous observations.19 In
Europeans believed caused the Black Death.11,17 People of 1898, Dr. Paul-Louis Simond in Karachi showed that fleas
that period thought warm baths permitted plague miasma to
from infected rats could transmit the disease to healthy rats,
enter humans’ pores, so public baths were closed. Victims’
and Ricardo Jorge in 1927 reported that wild rodents serve
clothes and possessions were thought contaminated and
as a plague reservoir.10
were burned, and cats were killed as possible transmission
agents. So-called “plague doctors” wore protective clothing
with a long cape, mask, and a bill-like portion over the CLINICAL PRESENTATION, TREATMENT, AND
mouth and nose containing aromatic substances (partly to PROPHYLAXIS
block out the putrid smell of decaying corpses), perhaps an There are 3 major clinical forms of the plague.10,21-23 In the
10
early version of the modern hazmat suit (Figure 1). most common bubonic subtype, infected persons develop
The third plague pandemic began in Yunnan Province in sudden onset of high fevers (>39.4˚C), terrible pains in
southwest China around 1855, where outbreaks had occurred their limbs and abdomen, and headaches generally between
since 1772, and spread to Taiwan.10,11,18 It hit Canton in 3 and 7 days after exposure. The bacteria reproduce rapidly
1894, where it caused 70,000 deaths, and then appeared in in lymph nodes located closest to the flea bites, leading to
Hong Kong. Ships carried it to Japan, India, Australia, and painful swellings (“buboes”) in the groin, cervical, or axil-
North and South America between 1910 and 1920.10,11,18 An lary lymph nodes, which can enlarge to the size of an egg
estimated 12 million people died from the plague in India (or up to 10 cm) (Figure 2)12. About 60% of untreated vic-
19
between 1898 and 1918. Rats from merchant ships brought tims die within 1 week of exposure as the pus-filled buboes
the plague to Chinatown in San Francisco in 1900.20 suppurate and the patient succumbs to overwhelming infec-
Although few European cases of the plague were reported tion.10,21-23 During the time of the Black Death, it must
4,20
after 1950, isolated outbreaks still occur worldwide. It is have been truly terrifying to witness otherwise healthy
178 The American Journal of Medicine, Vol 134, No 2, February 2021
Figure 3 Gangrene from plague sepsis. A man from Oregon
developed bubonic plague after being bitten by an infected cat,
leading to sepsis and acral amputation. Courtesy Centers for
Disease Control and Prevention.
individuals cut down rapidly by a seemingly invisible
demon. The rarer septicemic plague form (10%-15% of
cases) occurs when the bacteria multiply in the blood, often
triggering disseminated intravascular coagulation and gan-
grene of the extremities, ears, or nose10,21-23 (Figure 3).
Finally, the infrequent, fulminant pneumonic plague syn-
Figure 1 Costume of the plague doctor. The plague doc-
drome represents the only form with human-to-human
tor wore a black hat, beaked white mask, which contained transmission as inhalation of aerosolized droplets (much
aromatic substances to block out the smell of decaying like coronavirus transmission) from infected patients or
bodies, and a waxed gown. The rod or pointer kept even cats leads rapidly to hemoptysis and death. Because
afflicted patients away. The earliest version of a protective this clinical subtype is specifically aerosolized, pneumonic
hazmat suit. Courtesy National Library of Medicine. plague could be used for potential bioterrorist attacks.5,6,26
Its initially nonspecific, flu-like symptoms include sudden
onset of high fevers and dyspnea within 4 days of plague
exposure, progressing quickly to a purulent, frothy, or ulti-
mately bloody cough.21-23 Chest X-ray for primary pneu-
monic plague may show lobar pneumonia, which spreads
rapidly throughout the lungs. The blood-tinged sputum is
highly infectious.21-23 The latter 2 clinical subtypes are
invariably fatal without treatment.
Plague transmission is generally from infected fleas by
rodent vectors or, rarely, in clothing or grain but may also
occur through ingesting contaminated animals, physical
contact with infected victims, or direct inhalation of infec-
tious respiratory droplets.21-23 Early recognition and treat-
ment with streptomycin (or gentamycin) or a combination
of doxycycline, ciprofloxacin, and chloramphenicol can
cure the bubonic plague.21-23 One study compared the
plague fatality rate in the United States from 1900-1942
(before antibiotics were available) at 66% compared with
Figure 2 Buboes (swellings). Cervical buboes in a patient cases after 1942 and the advent of antibiotic treatments
with bubonic plague from Madagascar. From Prentice MB, with a death rate of only 13%.20 Prompt identification of
Rahalison L. Plague. Lancet. 2007;369:1196-1207. doi: plague infections and the introduction of appropriate antibi-
10.1016/S0140-6736(07)60566-2. Copyright Elsevier 2007. otics will generally lead to a full recovery, but because its
initial symptoms may include a nonspecific fever and often
Glatter and Finkelman History of the Plague 179
no clear exposure to infected animals or fleas can be identi- widely deployed to kill plague hosts, and potential mamma-
fied, diagnosis may be delayed, leading to death. The gold lian carriers were destroyed.26 Although such laborious
standard for diagnosis is isolation of the bacteria from tissue efforts decreased cases, the plague was never fully elimi-
or body fluids, which should only be done in a biosafety nated. The potential toxicity to humans and the native eco-
level 3 laboratory, although confirmatory serologic testing system from insecticides promoted a shift toward vector
for antibodies to the F1 antigen may also be performed.21-23 control (not eradication) and epidemiological sampling to
Empiric chemoprophylaxis with oral doxycycline or cipro- monitor the presence of Y. pestis in local rodent popula-
floxacin for 7 days is recommended for family members or tions.4-6,26 Current programs balance ongoing surveillance
others in close contact to victims of plague.21-23,27 There among plague vectors with protecting the natural environ-
was a whole-cell, formalin-killed vaccine, but it was dis- ment as a multipronged approach toward plague contain-
continued because it was only protective against bubonic ment.4-6,26
plague. Efforts continue to produce a vaccine effective
against the rare pneumonic plague subtype, which poten- PLAGUE AND BIOTERRORISM
tially could be used for biowarfare.5,6
The Centers for Disease Control and Prevention (CDC)
classifies Y. pestis as a Category A (tier 1) biologic agent
for potential bioterrorism.5 It can be released and spread
MODERN PLAGUE OUTBREAKS easily, which creates a major public health hazard and could
More than just a historical oddity, plague outbreaks con-
lead to quarantines and potentially widespread economic
tinue to surface and cause occasional deaths throughout the
devastation.5,6 Pneumonic plague leads to death rapidly
world.4,20 Plague reservoirs exist in animal hosts, including
without prompt recognition and treatment. Its initial non-
wild squirrels, rats, prairie dogs, marmots, gophers, and specific symptomatology of flu-like illness coupled with a
other rodents; cats can become infected and transmit Y. pes- mistaken perception that plague is simply an obscure, dor-
tis via aerosolized droplets.10,21-23 An outbreak hit Los
mant disease make it an ideal weapon for biowarfare.5,6
Angeles in 1924, killing 30 people, when a man contracted
Indeed, Tatars leveraged its lethality in 1346 by catapulting
the disease and died after handling a dead rat. A Catholic
plague-ridden corpses into the Genoese-controlled seaport
priest administering last rites to victims and mourners
of Caffa, in one of the first uses of biological agents to
attending associated funerals all also died of pneumonic
wage war.3 The Imperial Japanese Unit 731 during World
plague.28 The “telluric hypothesis” proposes that plague
War II developed and deployed biological weapons in Man-
bacteria can survive in soil and not simply on rodents, churia and China. On October 27, 1940, Japanese warplanes
which may explain why plague foci persist despite aggres- dropped plague-contaminated rice and fleas into Chuhsien,
sive efforts to eradicate its hosts.11 One recent analysis
China, which led to an outbreak of pneumonic plague.3,5,6
reported that Madagascar, Congo, and Peru remain the
The World Health Organization estimates that if only 50 kg
most plague-endemic countries.5 Indeed, between 2010 and
of Y. pestis were released in aerosolized form over a major
2015, there were 3248 cases and 584 plague deaths world-
city, the deadly pneumonic plague subtype could cause
wide, with the majority (75%) being in Madagascar.5
widespread devastation and death. The bacteria remain via-
Plague eruptions can disrupt production in modern econo-
ble for up to 1 hour at a distance of up to 10 km from the
mies, just as it did in the Middle Ages. In 2005, 130 men drop point.5,6 Because a main goal of bioterrorism would
working in a diamond mine in Congo contracted plague, be to incite fear among its population, plague is an ideal
causing 57 deaths. Similarly, 162 workers were sickened in
biological tool because its victims die quickly in a horrific
2006 at a gold mine in Congo, leading to 45 deaths and tem-
fashion (with hemoptysis, respiratory failure, high fevers,
porarily shutting down these operations.23 The World
and the like).
Health Organization (WHO) has deemed plague to be a ree-
merging disease since the 1990s.5 Two unrelated teens con-
tracted plague in separate incidents in August 2015 while FAMILIAL MEDITERRANEAN FEVER AND
visiting Yosemite National Park in California, apparently Y. PESTIS
from infected squirrels, although local bears also demon- Molecular advances have linked familial Mediterranean
strated antibodies against Y. pestis.29 Indeed, a healthy 15- fever (FMF) gene mutations to plague immunity.7,31-34
year old boy died in July 2020 from plague in Mongolia FMF is a rare, recessive disease mostly seen in people of
after eating an infected marmot (similar to a large ground Arab, Armenian, Jewish, or Turkish ancestry. Symptoms of
squirrel), and Mongolia has had almost 600 cases of mar- FMF include abdominal pain, arthritis, and fevers lasting
mot plague since 1928, with an associated mortality rate of 12-72 hours, although those affected are usually completely
74%.5,30 normal between spells.32,33 Pyrin is its gene protein prod-
Systematic attempts to destroy plague reservoirs largely uct, from the Greek word for “fever.” As an extremely
failed. For decades until 1991, the Union of Soviet Socialist important and versatile immune regulator, pyrin fights
Republics (USSR) launched an impressive, aggressive infection and cancer. When bacteria attack a cell, the
plague-eradication program. Poisons were placed manually immune system is activated. Pyrin is one of the major play-
into thousands of rodent burrows, pesticides like DDT were ers in this immune system cascade and plays a crucial role
180 The American Journal of Medicine, Vol 134, No 2, February 2021
in mounting and maintaining human defense systems medical, and social science aspects of plague pandemics
against pathogens. Pyrin activates caspase-1, an enzyme can lead us to greater understanding of the interplay among
that facilitates programmed cell death, and participates in history, humanity, and science.
IL-1b processing for fever production.8,31-33 Y. pestis
reduces production of IL-1b and IL-18, blocking the References
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