Thursday, May 19, 2011

Plague


Few words are as emotive in the world of public health as the Plague. Indeed, it is unique among diseases in that the invocation of its very name demands not only the name itself, but also the definite article. So embedded in the depths of the human imagination, this malady requires all others to stand upon the order of its own coming and going. The Plague. Even the font seems to shift and contort into grotesque features as you read the written word upon the page. The fixed and fantastically dull, Times New Roman, is transformed before your eyes into something only the fear of the memory of countless generations can transcribe:

The Plague.



But enough of hyperbole, why should this disease evoke such profound dread? First and foremost, it does not constitute a large-scale public health burden, or threat, so why the fuss? HIV/AIDS, tuberculosis, and malaria are the big three, which account for miillions of lives lost and immeasurable morbidity each year around the world. None of these, not even HIV as we currently live through its devastating pandemic, invoke the visceral response of plague. The loathsome neglected tropical diseases such as trypanosomiasis and leishmaniasis, which constitute large burdens across the developing world, can inflict horrible morbidity and mortality that devastates communities, but even these typically are not feared like the plague. The yearly varied influenza virus in all its forms, constantly renewing itself each season, does not even motivate most to vaccinate! The emergence of the superbugs, those virulent bacteria that have developed resistance to antibiotic therapy such as methicillin-resistant staphylococcus aureus, may instill an unequaled fear among infectious disease clinicians (quite justified, I might add), but they do not, generally, strike fear into the hearts of the general populace. Indeed, "plague" has such powerful connotation, that it has come to be used to refer to any severe epidemic of infectious disease.

So, wherefore this dread? Likely it comes down through our shared historical experience as human beings, and what was probably one of the first instances of a human pandemic (other early pandemics were probably due to smallpox). In fact, historically, there have been three plague pandemics. The First plague pandemic occurred from 541 to 542 AD and is known as the Justinian Plague, so called because it ravaged the Byzantine Empire under the rule of the emperor Justinian. Geographically speaking, it affected the Mediterranean, including southern Europe, northern Africa, and the near-Middle East, shown here in red:



Key to the emergence of this, perhaps first, pandemic disease (though, in reality this was probably second to a smallpox pandemic during the preceding Roman empire), were the extensive trade routes across very large geographic landscapes. As people traversed large geographic spaces by land and sea, they brought their trade goods with them...and their rats...and their rats' fleas. And so the widespread dissemination of plague was facilitated by trade.

The Second plague pandemic raged from 1347 to 1351 and is known as the "Black Death". It originated in central Asia and spread rapidly following the Silk Road: once again the pandemic emerged by way of the movement of people and their rodents along the routes of trade. The spatial-temporal spread of the Second pandemic is detailed nicely in this animated graphic:


This pandemic was truly devastating. It is believed that more than 100 million people died from this plague, which represented almost 25% of the global human population. No pandemic since has claimed the lives of such a large proportion of the human population. In addition, this pandemic affected very large areas, particularly China and Europe, where the infection killed about 1/2 and 1/3 of the populations, respectively. In these regions the incidence of pneumonic plague became relatively high as the infection became more established in humans. As such, human-to-human transmission became much more prominent, which is not typically how humans acquire the infection. It is worth restating the mortality above: this pandemic killed 1/2 the population of China and 1/3 the population of Europe. It also killed 1/8 the population of Africa. The scope of such a catastrophe is utterly incomprehensible to the modern world. All we can do is stare in amazement at the staggering statistics.

Perhaps with an historical perspective, we can start to get a sense of why this disease has been so feared throughout the human experience.

We are currently living through the Third plague pandemic. This began in 1855 in China and has killed more than 12 million people there and in India over the last one and a half centuries. This pandemic has spread to each continent with permanent human populations (i.e. excluding Antarctica). It was widely distributed as bubonic plague by shipping routes, with the domestic rats carried aboard shipping vessels transporting the plague bacteria to ports all around the world. Once again, plague followed the trade routes. East, Southeast and South Asia were widely affected up until the turn of the 19th century. The plague reached the United States in 1900 and accounted for urban plague outbreaks up until the 1920s. As described in detail below, currently the world's largest remaining sylvan focus of plague continues to exist in the western and southwestern US. Though most of the human cases do not come from there. Today the largest number of human cases (over 99%) come from sub-Saharan African countries. The Democratic Republic of Congo and Madagascar both see a particularly large number of cases, relatively speaking, as it is still a rare disease. One of the most striking demonstrations of the popular fear of plague that remains into modern times comes from Surat, India. In 1994 an outbreak of pneumonic plague resulted in 54 deaths in the town of Surat in Gujarat, India. During this outbreak, a staggering 300,000 people fled the area as the news of epidemic broke. This massive popular migration brought the local economy and social infrastructure to a standstill and created a humanitarian disaster. The epidemic also affected the larger national Indian economy because of the response of the international community and the subsequent effect on India's industries. Nevertheless, the Indian public health authorities should be applauded for controlling the situation quickly and efficiently. They effectively prevented the epidemic from spreading outside this area of Gujarat through intensive field investigation and kept the death toll to a minimum given the potential for how extreme a large-scale epidemic of pneumonic plague could quickly have become.

This gives a brief, and somewhat crude, history of plague, which I think is enlightening for this disease. This is not only because it has afflicted the human species for a long time. Many diseases have done so. Malaria, tuberculosis, and many other of the major killers of today have afflicted our species for millennia. But plague is a little different. Or rather, it sits a little differently in our collective imagination. This is probably because it represents some of humanity's first experiences with pandemics. Perhaps our first recognition of ourselves as a "global" species, as the trade routes opened vast geographies to local populations, also came with the recognition that we could be rapidly wiped-out in large numbers by an unknown scourge for which no corner of our shared landscapes was safe.  It seems to breed a unique cross-cultural fear that has been passed down in the recordings of many peoples across countless generations. We need look no further than 1994 and the panic that caused the movement of an entire local population in India and the brief collapse of one of the largest economies on earth. Such fear is completely unfounded given today's geographic contexts and pathogen ecologies, which will be described in detail below. But the fear, however unwarranted given plague's actual threat, undeniably lives in our memory.

So, on to the disease.

Plague is caused by a bacterium known as Yersinia pestis in the family Enterobacteriaceae. This is a gram-negative bacillus and is a facultative intracellular organism. Here is a picture of a group of Y. pestis:


Notice the strips of the rod-shaped bacillus structures.While this pathogen can be transmitted via open wounds or skin abrasion, and by lung secretions in the rare pneumonic form of plague, it is primarily transmitted as bubonic plague by another arthropod vector. In this case the vector is the rodent flea:


While there are several species of flea, Xenopsylla cheopis (common name, Oriental rat flea) is the most important vector for human transmission, though Nosopsyllus fasciatus (common name, Northern rat flea) can also spread disease to humans from the rodent reservior.

The mode of the flea vector transmission of Y. pestis is particularly interesting. Let's take a moment to discuss some of the important aspects of this arthropod, and then I will come back to its transmission of plague.

Fleas are quite fascinating creatures. They are very small, ranging from 1.5 to 3 mm in length. But they are superb jumpers. They can jump approximately 20 cm with respect to the vertical, and 30 cm in the horizontal plane, which means they can jump approximately 200 times the length of their body! As such, they are the second best jumpers in the whole of the known animal kingdom. They need this jumping capacity for locomotion because they are wingless and so do not fly, and they also need to be able to propel themselves through host hair or feathers. Fleas have extremely tough exoskeletons, which are capable of withstanding extemes of pressure (relative to their mass).

Here is an interesting video on the mechanics of the jumping flea produced by Discovery News:



The life cycle of the flea is unusual in that it is necessary to consider the organization and structure of an entire flea community in order to understand their ecology. The flea life cycle is comprised of four primary forms: egg, larva, pupa, and adult. While these stages are similar to other vectors we have discussed before (e.g. mosquitoes and sandflies), their population dynamics are quite different. Most notably are the weighting of the population by its individual life stages:


In the graph above notice a 10-fold difference in the proportions of adults and eggs in the flea community. Female fleas are prodigious egg producers, laying up to 50 eggs per day, and they do so directly on the host itself. The eggs are only loosely attached to the surface of the host, typically in hair or feathers, or on the skin. Since the eggs do not adhere to the host they easily fall off, usually becoming deposited where that hosts rests or sleeps. When the eggs hatch the larvae will withdraw to crevices, cracks, nooks and crannies, but nevertheles, remaining in close proximity to where the host rests. The larvae then begin to form a cocoon around them known as the puparium, which will serve as the protective shell in which the pupae develop before emerging as fully formed adults. Critical to this life cycle is that through each stage of development the flea remains close to the host, or, at least, to the host's resting place. Adults emerge from their cocoon when one or more specific signals is identified by the cocooned adult: the adult flea senses the host's movement; the flea senses pressure from the superposition of the host's body weight (thus the flea's need for a very hard body, which is highly resistant to pressure); the flea senses the body heat of its host; or the flea senses carbon dioxide released as its host breathes. Any of these signals can trigger the emergence of the fully developed flea from its puparium. However, until the flea recieves such signals, it will remain in the cocoon. It can survive for months in this state, without feeding, waiting out its host's return. Here is the general life cycle of the flea in a nice graph produced by the Centers for Disease Control and Prevention (CDC):


And here is a short video produced by the Blue Springs Animal Hospital and Pet Resort detailing the different stages of the flea life cycle:




So, returning to the flea as a vector for plague, we are left with the question: how do fleas transmit Y. pestis? It is a unique process, indeed. In fact, unlike most of the arthropod vector-pathogen relationships we have explored so far, the relationship between the flea and Y. pestis is NOT commensal, it is antagonistic to the flea. For example, the Anopheles and Aedes mosquitoes, which transmit the Plasmodium parasites and dengue virus, respectively, appear to be commensal with those pathogens. This means the pathogens do their host vectors neither harm nor good at the population level of the vector. They do harm once they are transmitted to the human host, but, on average, not to the vector. Fleas, on the other hand, are directly harmed by the plague bacillus, and, crucially, it is by this very mechanism of antagonism that Y. pestis can be transmitted to new mammalian hosts! Here's how it works:

When fleas take a blood meal from a host infected with Y. pestis, some of the fleas will in fact clear the infection altogether and will not be able to infect a new host. But other fleas in the population will become infected. In these infected fleas, the plague bacilli multiply in the midgut of the flea. After about 2 days, the Y. pestis colony begins to form a biofilm within the stomach, esophagus, and proventriculus, which is the sphincter that separates the esophagus and stomach of the flea. This biofilm continues to grow in subsequent days impeding the passage of blood from the esophagus to the stomach. At some point between approximately 3 and 9 days after the flea's initial infection the proventriculus will become completely blocked, and thus allows no passage of blood to the stomach. The flea repeatedly tries to feed but cannot pass the blood from the esophagus to the stomach due to the blocked gut tract. Instead, the host's blood mixes with Y. pestis in the esophagus of the flea and is regurgitated back into the open bite wound of the host, causing a new infection if the host is susceptible (i.e. not already infected). And the flea eventually dies of starvation. So Y. pestis is really no one's friend. You may think it a cruel world, but biology works and so there you have it.

The primary reservoir hosts for Y. pestis are rodents. Rodents and their fleas maintain the infection cycle in both sylvan and domestic rodents. This is very important for human transmission, as plague is essentially a zoonotic disease. Y. pestis is first and foremost a sylvan pathogen, with wild rodents acting as the primary reservoir in nature. However, as is so often the case in human disease ecology, anthropogenic manipulation of the environment first creates, then brings humans into contact with, fragmented landscapes. In the case of plague, it is not simply human encroachment, but the vermin (i.e. domestic rodents) humans bring with them. As domestic rodents share landscapes with sylvan rodents in peri-domestic ecotones that bridge natural habitat with agricultural or urban communities, so too do these rodents share the Y. pestis pathogen, thus maintaining a dual sylvan-domestic reservoir cycle. In settings of poverty, overcrowding, and poor hygiene, humans often share close quarters with their domestic rodents and thus become exposed to the rodent fleas that carry Y. pestis. These critical features of 1) the maintenance of the sylvan-domestic reservoir, and 2) the close proximity of humans to domestic rodents in conditions of poverty, have largely defined the disease ecology in local epidemics where Y. pestis is endemic in rodent populations. There are other critical factors for the emergence of large epidemics or pandemics, like the large-scale transportation of people and goods over trade routes (discussed above) or the transition from bubonic plague to pneumonic plague (discussed below), but the basic rodent disease ecology is fundamental for establishing human transmission.

Let's turn now to a discussion of the disease. 

There are three distinct clinical manifestations of plague. These three are bubonic, septicemic and pneumonic plague. When humans are infected with Y. pestis, the most common manifestation is the first form, bubonic plague. This is characterized by general malaise, fever, chills, myalgia and sometimes seizures. As you can infer, these symtpoms are fairly indistinct and so initial diagnosis can easily be missed if plague is not expected and if the signature characteristic is missing: the swelling of the bubos:



In bubonic plague Y. pestis invades the lymphatic system. In particular, this bacterium is able to evade the phago-lysosomal enzymatic activity of the host's macrophages (similar to the Leishmania parasites, you will recall). Once established in the lymph nodes, the bacteria multiply and cause localized swelling in the lymph nodes, which can eventually become necrotic. The lymph nodes most often involved are in the groin area, but any lymph nodes can be involved. The term bubo is derived from the Greek description of these swollen lymph nodes. The English word "booboo", used as a generic description of any sore or injury for children, comes from this very early Greek description of one of the signs of bubonic plague. Case-fatality from untreated bubonic plague ranges between 30% and 60%, according to the World Health Organization (WHO), and between 50% and 60% according to the Control of Communicable Diseases Manual, which is produced by the American Public Health Association.

Bubonic plague symptoms:


Septicemic plague is extremely severe and, if untreated, will almost always result in death. This form of plague occurs when the bateria enter the blood and begin to multiply here rather than in the lymph. Remember that Y. pestis is gram-negative, which means it is an important producer of endotoxins. In the case of this particular pathogen, the endotoxins are responsible for a disseminated intravascular coagulation when the bacteria enter the blood, which causes micro-clotting, especially in the periphery. This can result in necrosis in peripheral tissues with associated gangrenous hands and feet:


Because clotting factors become depleted, this coagulopathy simultaneously diminishes the host's ability to control bleeding, which results in hemorrhaging under the skin or in other organs such as the lungs. Death from speticemic plague can be extraordinarily rapid. Treatment is required within 24 hours of infection or the associated case-fatality is very close to 100%.

Pneumonic plague is a Y. pestis infection that involves the lungs. Like septicemic plague, pneumonic plague is much more virulent than bubonic plague. But unlike bubonic and septicemic plague, pneumonic plague is extrememly contagious directly between humans via airborne transmission.  Most cases of pneumonic plague in humans are secondary to bubonic plague, which, as described above, is primarily transmitted via the flea vector. However, once a human host develops pneumonic plague this person is capable of transmitting the infection through lung secretions, as droplets and droplet nuclei, that can spread through coughing and talking. When these aerosilized emissions are inhaled new infection occurs, resulting in primary pneumonic plague. While this mode of transmission is rare, in an epidemic it can play an important role in the rapid movement of the disease through populations. Indeed, pneumonic plague likely played an important role in the 14th century pandemic that caused the Black Death.

Pneumonic plague symptoms:


Untreated, pneumonic plague has a case-fatality similar to that of septicemic plague: very close to 100%.

In order to understand the epidemiology of plague we need to examine the geographic distribution of enzootic disease. By enzootic disease, we mean the the level of baseline, prevalent disease that is typically present in a single-animal or mixed-animal population. Enzootic disease is punctuated by epizootic disease, which refers to an increase in the number of animal infections above the normal baseline level of infection. These terms describe disease in animal populations and are analogous to the terms endemic and epidemic that we use to describe disease in human populations. Disease cannot be transmitted to humans in areas where there are no enzootic foci of infection because, as described above, Y. pestis is first and foremost a sylvan rodent pathogen. The following map, produced by the WHO, shows the geographic distribution of plague. Countries reporting plague are colored orange, whereas the enzootic foci within countries reporting plague are colored red:


The country with the largest enzootic foci of plague is the United States. Most cases of human plague in the US are acquired in rural settings, transmitted by rodent flea vectors, and present as bubonic plague. There has not been any urban plague in the US since the 1924-25 epidemic in Los Angeles. According to the CDC, there are about a dozen plague cases per year in the US, and anywhere between 1000 and 3000 cases per year worldwide. Therefore, even though the US has by far the largest enzootic foci of Y. pestis of any country or larger geographic area in the world, it contributes relatively few human cases of plague each year. Most of the human cases of plague throughout the 20th century came from central Asia, China, and South Asia, as well as Southeast Asia during the Vietnam war, but currently most humans cases of plague are coming from sub-Saharan Africa and, to a lesser extent, Mongolia:


The Democratic Republic of Congo contributes more than 1000 cases per year to the global total, making this the country with the most active foci for human plague in the world. The long term wars that have devastated this country, contributing to massive population movements and extremes of poverty, have probably greatly contributed to this active plague foci.

The peridomestic transmission cycle in rodents is the primary source of threat for human transmission in rual areas of Africa and South and Central Asia today. In these areas, relatively high rural population densities combine with the poor hygiene and crowding associated with poverty, which in turn conspire with the sharing of infected fleas between sylvan and domestic rodents. Thus, the cycle of the dreaded plague is maintained. 

44 comments:

  1. I found it most interesting that Pneumonic plague Y. pestis had an antagonistc relationship with Fleas. I was wondering since some fleas avoided being infected with Y. pestis, is there any signs of any genetic variations to that can thwart this relationship from happening or being less harmful to the Flea. I also wanted to know how was it known or discovered that rodents are the primary foci of transmission?

    Jamal Burke

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  2. Hi all-

    So, I studied a bit of the epidemiology of the Black Death in college, and I know that there's historically been a little controvesy over whether the responsible pathogen was in fact y pestis (although recent analyses with PCR have found evidence for the bacterium in medieval grave sites.) Part of this controversy was because there hasn't been any evidence of x cheopsis and the main host, rattus rattus in europe at the time of the second pandemic, and part was because of the virulence and seasonality of the disease. However, given the molecular biology evidence, how do you make the ecology jive? Pneumonic transmission? Different furry beast? Northern rat flea instead?

    Best, Robin Brehm

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  3. Sra. Brehm,

    I think pneumonic transmission probably had a lot to do with it. Throw in some poor sewage control in those days and close quarters, and you have a great person-to-person infection device. But also, there are apparently several other furry creatures that, according to the CDC, can act as reservoirs (squirrels, cats, etc) so perhaps it's possible one of these (and its associated pest) could do so too?

    -Matt

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  4. Robin,

    I have reading up a little bit on the the plague and some modern researchers attribute the second pandemic in Europe to a virus. One piece of evidence proponents of this theory cite was the prevalence of the black death in places like norway in the winter where the climate is not conducive to the modern plague. They also cite evidence against the pneumonic transmission theory by citing that this form has only killed .3% of the population in its worst outbreak. Definitely do not know enough to say if this theory is valid or not but just found it interesting!

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  5. Previous low case fatality stems from the fact that rarely have circumstances been right for widespread pneumonic transmission. But the circumstances were right during the black death and this probably did play an important role here. However, it is unlikely that the black death was one thing. It most likely arose from more than one disease process that could take advantage of the times. Nevertheless, one of the pathogens was, undoubtedly, Y. pestis.

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  6. Max et al- Well, diseases do change over time. I would buy that pneumonic plague could have been more important hundreds of years ago. The fact that the doctors of the time wore masks suggests to me an airborne component of whatever disease it was. I think that a behavior that was not beneficial in some way would not likely spread so widely by chance, even if the logical reasoning of the time was not that of our own.

    Also, it being a different thing (virus) in northern Europe would make lots of sense, because the CCR5 delta32 mutation has been traced to about the time of the Black Death and in Northern Europe, spread by the Vikings. http://www.ncbi.nlm.nih.gov/pubmed/14636691

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  7. Hi all, I was curious about the low prevalence of Plague in West Africa, the West Indies and Mexico, based on the maps shown. They all have (or had in the recent past )busy ports for trade and tourists ships, hot climates and conditions of poverty. Does anyone know if there is a difference in susceptibility of rodent species in various areas?

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  8. As I am reading the conversation here, my mind wandered towards immunology... could it be that the population during the plague were completely susceptible to this/these "new emerging" pathogen(s)..hence the widespread death? Sort of like how 1918 flu wiped out the "younger" demographic because they had "no prior" immunity to this type of flu?

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  9. Claire: it depends on when you are talking about...present day, or historically? If historically, then I don't think we can conclude that there were not episodes of bubonic plague in Mexico, West Africa and the Caribbean. Certainly there are some historical records of cases appearing in these areas. Detailed documentation is less apparent not because they were consistently absent but the outbreaks went unreported by those who were keeping track. If you are talking about the present day, then you have to keep in mind that the global distribution has largely been determined by where Y. pestis has been able to establish reservoirs in nature. The pathogen was given a great vehicle to its distribution by the global system of trade, but the pathogen ultimately had to find stable reservoirs anywhere that it was to take root, otherwise it would exhaust itself relatively quickly. Keep in mind that Y. pestis requires a sylvan transmission cycle for enzootic maintenance.

    Deanna: There is very little, if any, population immunity to Y. pestis. If the right conditions presented today (extremely unlikely), similar case-fatality could be expected.

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  10. Its sort of interesting that the only reason we learn about the plague besides the handful of cases a year and it is a curious footnote in history is because of its implications for bio-terrorism. Introduced into a dense, poor community and the implications would be deadly. By the time a quarantine is enacted many people have had contact with the sick and an urban environment can quickly become infected. Given the history of using plagued corpses to infect cities we should not forget it's potential. Strains that are increasingly resistant to antibiotics keep coming up and most modern doctors would not know what it is for days after infection, giving time for the infected to spread by modern trade routes, all over the world.

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  11. It is amazing how destructive of a pandemic the plague turned out to be. It is curious that such a virulent pathogen does not still wreak more significant havoc if it still exists and was truly responsible for wiping out a quarter of the world's population.

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  12. It is frightening that the case fatality rate for plague is so high. It is more frightening that even with current treatment regimens (namely antibiotics) the case fatality rate is 10-20% for bubonic plague and 50% for pneumonic plague. Interestingly, a killed whole cell vaccine was developed and given to soldiers during the Vietnam War (because Vietnam is an endemic plague area). However, its efficacy remains unknown.

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  13. Hi All,

    During the past couple of weeks, the bubonic plague has recently garnered some attention in the US due to the case of a 7-year-old girl, in Colorado, who contracted the disease after burying a dead squirrel and subsequently being bitten by fleas. After becoming sick she was taken to the ER where doctors treated symptoms but couldn’t seem to identify the actual problem. After taking a thorough history, collaborating with other physicians, and transferring the girl to another nearby hospital they were eventually able to correctly identify the disease and treat it. Long story short, the little girl is doing fine and was sent home.

    Some of the things I found interesting about this particular case:
    - It shows that human cases of the disease are still rare within the United States even though there is a large disease presence in animals.
    - The manner in which the physicians were able to diagnose and treat a rare and seemingly non-existent disease, which had only been read about in textbooks.
    - The availability of many resources within and between hospitals that allow for effective treatment of cases.
    - The way some media outlets handled their reporting of it. (ABC News gave a decent play-by-play of events and I was surprised.)

    I thought it was a nice feel-good story, which is a rarity when it comes to the plague so here's a link to it:
    http://abcnews.go.com/Health/girl-bubonic-plague-saved-quick-thinking-doctor/story?id=17170384

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    1. As Rukhsana suggested, I also reviewed the case in Colorado in which a girl with disseminated intravascular coagulopathy due to severe Yersinia pestis infection survived as a result of re-interviewing the family into her risk factors. Knowing that septicemic plague is extremely severe and is fatal if not treated, her survival can be attributed to the medical staff diligence and the benefits that come as a result of advanced medical support. I was also wondering why there are not more cases in the US, more than the 10 or so a year? In contrast, what makes the Democratic Republic of Congo so vulnerable? The WHO reports that the Médecins sans Frontières is actively working to assess the situation and provide support. Despite isolation wards, contact tracing and chemo-prophylaxis of close contacts, control measures have been difficult to implement because of security concerns in the area. (http://www.who.int/mediacentre/ factsheets/fs267/en/) I was thinking that one solution could be to vaccinate the communities that are at high risk, similar to the way vaccines are used to protect high risk laboratory personnel.

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  14. So... I found this article very interesting and informative. I am quite surprised by the devastation the various forms of the plague are capable of causing. I think that given the right conditions especially crowding, unsanitary conditions and poverty (causing rodents and fleas) the plague can easily reappear. The fact that this disease will kill those infected within a few days of transmission - it is a very scary disease and now it is clear why it has gotten the well deserved term "plague" ("Black Death - in the 14th century).

    Y. Pestis bacteria is transmitted by fleas and rodents which bite a human and transmit the bacteria. It is interesting that depending on which part of the body the bacteria infects will determine what type of plague will ensue.

    Pneumonic Plague will occur when the lungs become infected and is easily transmitted via respiratory droplets. This type of the plague is the most easily transmitted between humans and therefore is therefore probably the most easily spread within populations.

    Bubonic and Septicemic plague is that is spread by bytes of fleas and rodents and occasionally can be spread from a contaminated article and an open sore spread by being bitten by an infected flea or rodent. Since the transmission is caused by bytes I believe that these forms of the plague can be controlled much easier than the Pneumonic plague

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  15. The historical context of the plague gives it mystique in the world of infectious disease. Everyone learns about the devastation of the plague in their 8th grade social studies class. One thing I thought about as I was reading this article was that middle school teachers and textbooks often present the plague as a problem of the past, eradicated by modern medicine. Clearly this isn't true.


    While on the topic of history, I found an editorial with an interesting , positive take on the history of the plague:

    In the early 14th century banks in Florence engaged in a large-scale credit expansion. This set the stage for a powerful economic upswing, which transformed Florence into the most important centre of finance and trade in the Mediterranean region. But the bankruptcy of England, a repatriation of funds to Naples and a bust of Florentine government bonds ended the credit cycle and triggered a crisis. Banks crashed and credit contracted. Real estate prices declined by 50%. It took thirty years—from 1349 to 1379— before a recovery began. Historians ascribe a role to the plague in recovery, which dramatically raised cash balances per capita (by lowering the denominator) and induced people to spend (by dramatically raising the discount rate for future consumption). As a result, deflation ended and output recovered. (From: http://www.businessinsider.com/bubonic-plague-saved-14th-century-europe-2013-5)

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    1. Allison GrossmanJune 20, 2013 at 5:51 PM

      Matt,

      Your comment about the misconception that the Plague is "over" resonated with me. I remember being very surprised the first time I saw the Plague on a differential list in a model medical context (I think it was the Dr. Sanders' "Diagnosis" column in the NYT).

      I don't usually think about the positive economic impact of disease, but you raise a good point. Industry depends on the search for novel procedures and treatments, and physicians earn their livings distributing the treatments and performing the procedures we already have. WIthout human disease, or infectious disease, a lot of people would be out of work.

      On another note, I wonder how raising cash balances per capita by lowering the denominator would have any real economic impact. I don't really understand how it's not different than inflation, assuming that everybody had a roughly equal probability of dying from the disease. Maybe, instead, people spent more because they felt their remaining days were limited?

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    2. Regarding the idea of the plague being the turning point between the so-called Dark Ages and the Renaissance in Italy, it wasn't the disease itself, but rather its consequences--one-third or so of the population was eliminated. It might be incorrect to assume everyone had an equal probability of dying; the greater burden of death and disease may have been, as usual, on the lower classes.

      Even if deaths from the plague were randomly distributed, lowering the denominator means a lot of people died, but their assets (namely, land) were still there for the taking. Also, since there was a labor shortage, wages rose, eventually leading to increased consumption. This is different from inflation, where prices rise without a change in population. What was a formerly stagnant situation (feudalism) became more or less a blank slate, with the wealth redistributed. It's not too much of a stretch to imagine a new, more productive system emerging from this situation, given clever bankers and an ambitious population.

      Nevertheless, it is difficult to define the true role of the plague in the development of Europe. There are some cases where a dramatic decrease in population could be considered helpful (great emigration waves from Ireland after the potato famine), but again, it may just be regression to the mean.

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    3. I would add that it's because the fall of Italian city states and the depopulation of southern and central Europe, the ottomans were able to invade Constantinople, and the Spaniards Andalusia. These 2 events are very significant to shaping the world as we know it now.

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  16. I wasn't aware that cases of plague still existed. I've always thought it was a disease of the past. I was intrigued by the fact that Y. pestis is just as damaging to fleas as it is to the host. Is there a reason why some fleas clear the infection immediately?

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    1. From what I have read it appears that Y. pestis causes a blockage essentially starving the flea. The bacteria is regurgitated by the flea while feeding on the host and that is how it enters the body. For the most part fleas die from starvation and dehydration, but it has been found that when the temperature rises, the blockage is less likely to occur in the first place which might be why some fleas survive.

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  18. Sheaba Daniel
    I am shocked, like other readers, that the plague is a still present disease. The way that it was taught in history class, it seemed as if the Plague was a disease of the past.
    It is interesting to note that Y.pestis has changed very little over 600 years.
    I wonder if there is any scientific evidence as to why the "Black Death" strain was so deadly compared to the modern strain. other than changes in hygienic and environmental factors.

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    1. I think the “Black Death” seems more deadly compared to the modern plague because 1) pneumonic plague (based on the article) facilitated the rapid spread of the disease among populations; 2) many deaths resulted from the lack of proper treatments as the case-fatality of pneumonic plague is very close to 100% if untreated. While reading the article, I was wondering how the US is able to maintain human cases of plague at a lower number even though it has “the largest enzootic foci of Y. pestis in the world”. But I think in addition to the environmental factors and advanced medical knowledge, the readily available resources and the full media coverage of an re-emerging case as Rukhsana mentioned earlier help the control of the disease.

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    2. Wen I think your suggestions as to why the US maintains such a low incidence are spot on! We have the advantage of having advanced medical knowledge and technology that help quickly identify the disease and media coverage allows people to become aware of what is going on.

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    3. Sarah and Wen D, I do agree with both of you in regards to how the US suppress this disease. The availability of a wide range of laboratory testing and antibiotics is a huge contributor when compared to countries without these luxuries.
      From the stand point of a medical provider, I must say that on initial assessment of a patient with the plague, it would be very difficult to diagnose for two main reasons: 1. without the pathognomonic lesion, the symptoms are very similar to many other diseases; 2. given that the disease is so rare (in this current age), one would not think about the plague as the initial diagnosis.
      Especially in the emergency room, when the source of infection is unknown, most patients are started on broad spectrum antibiotics to cover for both gram positive and gram negative bacteria, until they have full workup. With this in mind, I wonder if the prevalence is higher in the US, but are just masked by the way we practice medicine.
      Another factor to note is that for most part, the US has a good sanitation system leaving little room for rodents to breed and live. In addition, most other host animals such as dogs and cats are domesticated (and not wild) with good hygiene, leading to a significant decrease in flees.

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  19. I heard about the plague, but didn’t realize how severe it was. Reading this article and taking note of the statistic, that is, wiping out 25% of the human race is beyond belief.
    I want to add a little with respect to diagnosis and treatment because as I was reading, I wanted to know, apart from identifying symptoms, how can we confirm that it is the plague and once confirmed or suspected, what is the treatment?
    For diagnosis, specimen should be taken directly from the suspected source for culture (including blood, sputum, bronchial/tracheal washings and lymph node aspirate).
    Staining and direct visualization under a microscope is mostly used. “Visualization of bipolar-staining, ovoid, Gram-negative organisms with a "safety pin" appearance permits a rapid presumptive diagnosis of plague.”
    Serologic testing may also be done to confirm diagnosis.
    For treatment – given that it is a gram negative bacteria, antibiotics that target gram negatives should be used. The drugs of choice are Streptomycin or Gentamycin. However, if these are not available, tetracyclines, fluoroquinolones and chloramphenicol may be used. The usual course is 10 days.

    Reference: CDC: Plague – Resource for Clinicians. Accessed at http://www.cdc.gov/plague/healthcare/clinicians.html

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  20. I found this article especially interesting in light of the report of a man dying from the bubonic plague in China recently (1). As Professor Walsh mentions in the article, there is an overwhelming visceral response to hearing about the plague. Chinese authorities have blockaded the town where the case occurred in attempts to stem mass panic as occurred in India’s epidemic in the 1990s. The town has enough basic food supplies to last a month and is setting aside 1 million yuan ($161,200) for an emergency program to vaccinate citizens (2). They have also quarantined the 151 people who had direct contact with the man. As professor Walsh mentioned, such exaggerated responses may be costly if the man did not die of pneumonic plague, the type that is able to be transmitted between humans. Of more concern to authorities ought to be controlling the threat of human transmission from rodents, or in China’s case, marmots (a large squirrel).

    (1) http://sinosphere.blogs.nytimes.com/2014/07/23/town-in-northwest-china-sealed-after-man-dies-of-plague/
    (2) http://www.dailymail.co.uk/news/article-2701641/Parts-Chinese-city-quarantined-resident-dies-BUBONIC-PLAGUE-bitten-rodent.html

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    1. Hi Mohammad,

      I just read this article too and was going to make similar comments on the handling of the situation by the Chinese government. Like you mentioned the man didn't die from the pneumonic plague infection which can spread from person to person and this precaution of quarantining those infected will not help with the actual prevention of the bubonic plague. I think there is a political aspect to this case in particular since it does involve China and this response is more to alleviate fears and the mention that they are providing supplies is to show that they are providing for these people. However, looking at it in the public health prospective, this man was in contact with a dead marmot which he fed to his dog and there is no additional cases. I think its interesting like you mentioned how even today that there is still this fear of just the mention of the "plague" to cause such a response

      http://www.huffingtonpost.com/2014/07/22/china-bubonic-plague-death-yumen_n_5609908.html

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  21. I am interested in how several waves of this disease outbreak had a major impact on the course of European and world history and the rise and fall of different empires.

    Looking through some online resources, mostly Wikipedia☺ I read some about that and here is a sample of what is out there,
    “The plague's long-term effects on European and Christian history may have been enormous. As the disease spread to port cities around the Mediterranean, the struggling Goths were reinvigorated and their conflict with Constantinople entered a new phase. The plague weakened the Byzantine Empire at a critical point, when Justinian's armies had nearly retaken all of Italy and the western Mediterranean coast; this evolving conquest would have reunited the core of the Western Roman Empire with the Eastern Roman Empire. Although the conquest occurred in 554, the reunification did not last long. In 568, the Lombards invaded northern Italy, defeated the small Byzantine army that had been left behind, and established the Kingdom of the Lombards. This began the fragmentation of Italy, which lasted until the Risorgimento of the 19th century.”
    I will do a more detailed research regarding the effect of major disease outbreaks on history of the world and keep you posted ☺

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    1. I would add this for the black death that swept Europe in the 14 century:

      "This dramatic fall in Europe’s population became a lasting and characteristic feature of late medieval society, as subsequent plague epidemics swept away all tendencies of population growth. Inevitably it had an enormous impact on European society and greatly affected the dynamics of change and development from the medieval to Early Modern period. A historical turning point, as well as a vast human tragedy, the Black Death of 1346-53 is unparalleled in human history."

      http://www.historytoday.com/ole-j-benedictow/black-death-greatest-catastrophe-ever#sthash.vgTIEonH.dpuf

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  22. How can one distinguish between normal cases of pneumonia and pneumonic plague out side of its initial transmission through infected rodent contact. Based on the secondary transmission from human to human from droplet transmission, how is one able to tell? Also, I was shocked to see that there have been recent cases this past summer, one in Colorado and in China. What measures have been taking or may be currently in development, in preventive from more cases from spreading?

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    1. Hi Ashley,

      It's really hard to distinguish between the two. If the local doctors are not used to seeing plague, odds are they will not be able to identify it (like many other diseases). It seems that the only way to fully determine the presence of pneumonic plague is to conduct a culture - which unfortunately may prove to be too late for the infected individual and many of the potential secondary transmissions.

      Establishing control measures is also extremely difficult. With the proliferation of fleas among sylvan and domestic animal hosts, control becomes damn near impossible. The best thing we can hope for is making sure no areas have enormous population densities and individual based rodent control (e.g you set up traps and prevent infestations). Which is why, I think. even though the United States has the most number of foci, it has a minimal incidence of disease. The specific parts of Africa mentioned above, however, are not as fortunate.

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    2. I too find this worrisome especially if pneumonic plague reaches the prevalence it did in the 15th century. A fundamental aspect of identifying an outbreak is gaining a handle on clinical manifestations and if physicians are unable to differentiate between traditional pneumonia infections (typically treatable in otherwise healthy individuals with access to healthcare) and pneumonic plague it can be quite problematic. Generally physicians won't have the time or means to exhaust all tests and take unnecessary cultures to rule out plague when it is not endemic of a region.

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  23. Very informative article! I did not know that the second pandemic plague claimed the lives of approximately 1/2 and 1/3 of the populations of China and Europe, respectively.
    A few things I found interesting were:
    1. The historical context surrounding the first and second pandemic plagues.
    2. The animated graphic showing the spatial-temporal spread of the Black Death.
    3. The detailed description of how fleas transmit Y. pestis and the explanation of the antagonistic relationship between the flea and Y. pestis.
    4. The clip about the life cycle of a flea.

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    1. This article is informative and I also found the points you listed to be interesting too. I am not sure if they are listed in a particular order, but what you listed as number one stood out to me the most. Other comments to this article also include fascination about the history of plagues.
      Plagues are beyond detrimental compared to typical pandemics and devastating morbidity and mortality. History is important when understanding the first occurrence of a human pandemic which was considered a plague. The article mentions that one of the first pandemic disease, were the wide trade routes across extremely large geographic landscapes bringing their goods and disease. It is interesting to see a reoccurring theme. The second plague pandemic known as the “Black Death” was also due to movement of people along trade routes. Also, it is stated that the current plague pandemic was widely distributed as bubonic plague by shipping routes, and rats carried aboard transported the plague bacteria to various ports. Although there are other modes of transmission, it is a good demonstration of how history repeats itself with the first few plagues.

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  24. I have always found the Plague to be a fascinating disease. Like this post states, it brought millions of people to death, and at one point, it wiped out 25% of the global population. As of late, there have a been a smattering of cases of human plague reported in West/Southwest in the US. According to an MMWR in late August of 2015, 11 cases were reported since April 2015 in the US. The WHO has also declared an outbreak of the plague in Madagascar with 14 reported cases and 10 deaths as of August 30th of 2015. It seems like there are these satellite outbreaks of the plague which tend to fizzle out. This seems to be in direct relation to how it’s relatively rare. Unfortunately, like many infectious diseases, this disease is closely related to poverty and poor living conditions. While I’m assuming that elimination is impossible for a disease like this, if public health officials and policy implement interventions to reduce disease risk through proper sanitation, house disinfection, and vector control, could the disease burden be reduced to virtually nothing?

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  25. This was definitely an interesting read that has changed my perception of what the plague actually is and how it works; from the primary reservoir host and their fleas to humans. Prior to reading this post, when I heard the word “plague,” I immediately thought bubonic plague where the Y. pestis invades the lymphatic system and people get the “signature characteristic” of the swelling of the lymph nodes (buboes). Nonetheless, I did not consider that there are actually three distinct clinical manifestations of plague (bubonic, septicemic and pneumonic plague). The septicemic plague (bacteria enters the blood) requires treatment within 24 hours of infection since it can lead to an extraordinarily rapid death and the pneumonic plague, which is “extremely contagious directly between humans via airborne transmission,” has a case-fatality similar to that of septicemic plague (close to 100%). Another interesting point I was not aware of is that in order to comprehend the epidemiology of plague, the geographic distribution of enzootic disease must be examined. It is crazy to know that the plague represents some of humanity's first experiences with pandemics, from the Justinian Plague to the Black Death, which affected more than 100 million people. Even today we can see how deadly the plague can be where even though few cases are reported yearly, there are still unexpected ones such as the Taylor Gaes case, where the 16 year old contracted the septicemic plague from fleas on a dead rodent or another animal on the family's land and died. However, there are other cases, such as that of a Michigan resident that contracted the rare life-threatening bubonic plague, who is thankfully recovering after hospitalization and diagnosis (first ever bubonic plague case confirmed in Michigan). According to the CDC’s MMWR from August 28, 2015, there have been 11 cases of human plague reported in residents of six states since April 1st, including: “Arizona (two), California (one), Colorado (four), Georgia (one), New Mexico (two), and Oregon (one)” (2015). The links for these two cases and the CDC’s MMWR are: http://www.freep.com/story/news/2015/06/20/officials-say-rare-form-plague-killed-poudre-student/29031569/, http://www.freep.com/story/news/health/2015/09/14/bubonic-plague-case--michigan/72273070/, and http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6433a6.htm.

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  26. From a genetic standpoint, are there any known mechanisms/genes that allow the reservoir, i.e. the rat, to survive while the bacterium flows in its bloodstream?

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  27. I am convinced that there are two different diseases here. Y pestis causes bubonic plague which is still around, but the Black Death had different symptoms, different transmission and very different mortality rates. I think this is very important to clarify because we should know exactly what caused a third of humanity to be wiped out.

    A Journal of a Plague Year was written by Daniel Dafoe about living through the 1665 outbreak in London. I read this during the recent Ebola outbreak and I couldn't help associating the two. I think the Black Death was far more likely to be a viral hemorrhagic fever spread through human contact than Bubonic plague. I have also read that researchers have studied early Parish records in England to understand the mortality patterns which fit more with a human contact disease than a vector-borne.

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    1. But wasn't the Black Death the plague in its pneumonic form? Since people lived in such close quarters during that era, it would have been easy for a pathogen manifesting in lung secretions to be passed to someone else via coughing or talking. The pneumonic form of the plague is very contagious and with people not practicing or even knowing about proper hygiene practices back then, it is quite conceivable that pneumonic plague could have spread so quickly, to so many people.

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    2. Hi Edith,

      I chose this post because I just finished the book "Rats" by Robert Sullivan and he makes a number of arguments in favor of vector borne Y. pestis as the culprit for those plagues attributed to it. One interesting one is the correlation of surplus crop years to outbreaks of plague. This would be related to an increase in the rat population.

      While pneumonic transmission and other diseases (anthrax seems to be a popular alternative theory) could have played a role in the high death rates, it's worth remembering just how many rats there are living anyplace that humans do. The CDC still today does surveys of the NYC rat population to check for, among other things, plague infections.

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  28. First, I enjoyed the introduction, which I ask why you call it a hyperbole? Its important! Albeit not characteristic of the other article I read on Landscapes.
    I found it interesting that with the spread of goods comes the spread of evils. As soon as humans started traversing the globe to new locations, disease was brought with them. Perhaps one can argue the really “vector” is trade (business)!
    I also found the relationship between the fleas and the Y. pestis interesting in that it is an antagonistic relationship for the fleas and they end up dying from Y. pestis if they don’t clear it. It is the very harm that requires the flea to infect humans. If the flea would not be effected by Y. pestis, it wouldn’t have to regurgitate the blood and mix its own blood with that of the human.

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    1. I found the discussion regarding how fleas jump quite fascinating. Hey, I never even thought of fleas as jumping, let alone did i ever wonder if they used their knees or feet to jump.

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