Yersinia Pestis

00:01 On this slide, we’ll talk about the natural transmission of Yersinia pestis and starting with the flea and the rodent.

00:10 It participates in what is known as a sylvatic transmission cycle, cycling between the flea and the rodent. The flea takes a blood meal from the rodent and in the flea the organism grows, does its thing and then it’s transmitted back to the rodent's bloodstream via the bite of the flea, back and forth, back and forth.

00:32 Occasionally, an amplifying host such as another warm-blooded mammal like the raccoon will be involved in the cycle and because it’s a larger animal with a more robust immune system, the organism load the number of Yersinia bacteria within a specific aliquot of blood will increase in density.

00:54 At some point, this natural transmission between flea-rodent and other mammals will exit accidently into a human.

01:04 On the left side of slide if it is due to a direct contact with a bite either from the infected rodent or raccoon or the flea it will cause a specific bubonic plague infection which in general creates a localized site of inoculation and then an infected lymph node which is proximal to the site creating a bubo.

01:31 Bubo simply means a lymph node which has been processing and growing Yersinia pestis, developing in size and eventually becoming clinically significant.

01:43 On the right side of the slide we can see the exit of the sylvatic transmission cycle into a human via a flea bite or direct contact but in some way creating an aerosolization or an aspiration of the Yersina pestis.

01:59 Now the patient has a pneumonic or pneumonia form of the plague and can become quite contagious creating airborne transmission to other humans.

02:10 So, as with other infectious agents and Ebola virus would be one example, normal sylvatic transmission within the animal kingdom and the insect kingdom occurs, humans are accidental host.

02:24 Pathogenesis.

02:27 What happens after that accidental transmission to the human? First, the Yersinia pestis is phagocytosed by a monocyte or a macrophage, not a neutrophil, and after so doing it is able to avoid killing within that macrophage as we’ve seen with other organisms.

02:47 It’s able to prevent fusion of the lysosome or enzyme containing vacuole with the phagosome where the organism lives.

02:56 Within the macrophage it then is able to proliferate and grow in number as you see to the right side of the image.

03:03 Also, the macrophage, either already fixed in a lymph node or as a mobile dendritic cell is able to travel to the lymph node in proximity to the site of inoculation and there one can see ongoing proliferation of further infected macrophages which will then increase the size of that infected lymph node.

03:27 At some point, the Yersinia pestis is able to release exotoxins which cause further cellular damage and further recruitment of lymphocytes and even some neutrophils which then increases precipitously the size of that infected lymph node turning it into the bubo that we just discussed, and then further dissemination can occur into the blood stream.

03:52 So if we compare the forms of the plague. In the middle column pneumonic plague, on the right column bubonic plague.

04:00 The transmission is simply how the patient is exposed to the Yersinia pestis.

04:06 In pneumonic plague it will be some form of inhalation of infectious droplets either by being exposed to aerosolized respiratory droplets from a mammal for example a prairie dog in a prairie hole or by inoculation via bite of a prairie dog or bite of the infected flea, that would be for bubonic plague.

04:29 The incubation period for pneumonic plague is quite rapid, two to three days, and in a case of a bioterrorist attack, some cases can be rapid as one day because the inoculum, the amount of organism which was aerosolized and delivered to the victim was quite large.

04:48 In bubonic plague, seven days is the number of days for typical trans - excuse me, for incubation - only because it's a small amount of inoculum which then must travel retrograde to the proximal lymph node and start to develop the bubo.

05:04 The signs and symptoms are also somewhat different.

05:07 In pneumonic plague, the fever malaise is quite prominent as you would anticipate in a flu-like illness, but after that first day of fever, the patient rapidly develops respiratory not just problems but respiratory failure over the course of one to two days, they may require ventilation and respiratory support.

05:27 In the bubonic plague, the fevers start, followed in a gradual process by that painfully swollen lymph node, the bubo.

05:35 Most buboes are found in the groin or in the axila because most inoculation sites or bites occur on the distal extremity - legs or arms.

05:46 After a certain amount of time and this could range from several days to up to a week, the patient may then develop secondary signs of infection including conjunctivitis, rigors with the fevers along with the bacteremia.

05:59 Untreated infection by Yersinia pestis is quite fatal. Untreated pneumonic plague almost 100% of patients will die and bubonic plague at least ¾ of them will die, 75%.

06:13 The third form of the plague is septicaemia plague, which is defined as having no bubo or other localising signs, and therefore this can be quite difficult to recognise. Note, however, that septicemia is still common with the other forms of the plague.

06:28 Septicemia plague accounts for 10 to 20% of diseases caused by Yersinia pestis and again is characterized by that absence of localizing signs.

06:37 It is transmitted by the bite of an infected flea, and after an incubation period of several days, patients will develop fever and become very ill appearing bordering on toxic.

06:48 They may have nausea, vomiting, diarrhea and non-specific abdominal pain.

06:53 Again, a very difficult illness to diagnose up front.

06:56 However, later on, the disease progresses into hypotension to shock disseminated intravascular coagulopathy or disc and multi-organ failure.

07:05 Unfortunately, in the absence of treatment, septicemia plague has a very high mortality rate greater than 90%.

07:12 But with treatment, the mortality rate is less than 15%.

07:17 The rule of thumb for Yersinia pestis is that if you have a high clinical suspicion, start your treatment, start your antibiotics without waiting for the diagnostic test to result.

07:27 Clues to consider would be your clinical suspicion.

07:30 So compatible clinical illness, fever, unexplained lymphangitis, hypertension.

07:36 Having pneumonia with him.

07:38 Ptosis and a gram negative rod, of course, but especially picking up travel to an endemic area and a recent animal contact, especially a rodent exposure. So this again is another example of taking a very good and thorough history. Cultures can be obtained from most body fluids, so blood, sputum, cerebrospinal fluid or the buboes.

07:59 And then rapid tests are done using antibodies, monoclonal antibodies to the F one antigen.

08:05 However, those tests, of course, can be expensive and time time significant.

08:10 Other forms of testing include serology, such as your ELISA enzyme linked immunosorbent assay and polymerase chain reaction your PCR.

08:19 But those also have longer processing times on the slide.

08:24 On the right we see a photo micrograph of a right stain blood specimen from a plague victim, which shows the presence of Yersinia pestis.

08:31 And you can see those bipolar ends that are darkly stained the red arrow in the lower right part of that slide.

08:36 It looks just like a safety pin.

08:38 Again, a good key factor to remember for testing.

08:42 So what can we do about Yersinia pestis? First and foremost, pest control and in fact as we control not just the fleas but also avoid exposure to infected rodents.

08:56 We also need to be aware that this is a very contagious organism so a patient who has been exposed for example, somebody traveling in a prairie dog haven who might have been exposed needs to be monitored carefully for signs and symptoms of pneumonic or bubonic plague and if they start to develop them put into isolation.

09:18 So pest control, very important, isolation - even empiric and early isolation is very necessary.

09:26 There are vaccines available although their validity and efficacy remain to be established.

09:32 They do appear to be effective against the bubonic plague but keep in mind that there were very small numbers used to test the success rate of those vaccines.

09:42 Treatment.

09:43 Empiric treatment, meaning before confirmation of the diagnosis is most likely to be successful again because the mortality or death rate for both forms of the plague is so severe.

09:56 Streptomycin or gentamycin are the two possible drugs which are most efficacious.

10:02 If the patient may have underlying renal failure which would compromise use of an aminoglycoside like either streptomycin or gentamycin then use of tetracyclines and chloramphenicol might be useful as well.

10:15 In fact, as an empiric choice, a drug-like tetracycline or doxycycline which might cover other vector borne infection such as tick associated diseases maybe the most initially effective. However, after confirmation of infection of Yersinia pestis, transfer to an aminoglycoside is the way to go.

10:36 Fluoroquinolones are also accepted as first line treatment and those include levothyroxine, ciprofloxacin and moxifloxacin.