Tuberculosis | Clinical Medicine

0:01[snorts]

0:08>> What's up Ninja Nerds? In this video

0:09today we're going to be talking about

0:10tuberculosis. And if you guys like this

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0:20it out, there's a lot to learn. All

0:21right, let's get into TB. When we talk

0:23about TB, first thing we need to know is

0:25what's the thing that's causing it? What

0:26is that particular pathogen? The

0:27particular pathogen is actually called a

0:29mycobacterium tuberculosis. That's

0:32really, really important to remember.

0:33So, the primary pathogen is called

0:36mycobacterium bacterium

0:39tuberculosis.

0:41Now, there's a lot of different types of

0:42mycobacterium species.

0:45But, mycobacterium tuberculosis is

0:46definitely

0:48it's a pretty scary one. When we talk

0:50about this one, what makes this one

0:51super unique is when you actually zoom

0:52in on its overall cell wall, there's a

0:54couple different components that are

0:55really critical. So, going from the most

0:57inner portion to the outer portion,

0:58there's a couple different layers. One

1:00here we have just the overall cell

1:02membrane.

1:03All right, that's kind of that just a

1:04phospholipid bilayer, if you will. Then

1:07after that, we have this peptidoglycan

1:09layer, all right? So, then we have

1:10something called a peptidoglycan

1:14layer.

1:16Then, there's technically a something

1:17called arabino

1:20galactan

1:22layer.

1:23And then the most important layer is

1:25called the mycolic acids. So, this is

1:27called mycolic

1:30acids. Now, the mycolic acids are

1:33probably the most important thing to

1:34remember. When we talk about this one,

1:36mycolic acids, really what's interesting

1:39about these

1:40is that they allow for mycobacterium to

1:43be

1:44I'd say whenever you're doing your

1:46special types of staining, so when you

1:47go through your different types of Gram

1:48staining procedures, you use things like

1:50crystal violet, you use things like

1:52carbolfuchsin, and generally what it's

1:53supposed to do is supposed to stain the

1:55bacteria kind of like a

1:57reddish pinkish color. And then what you

1:59do is you actually undergo a process

2:01where you kind of use this kind of acid

2:05alcohol to decolorize it and remove that

2:07dye out.

2:08What happens with mycolic acids is that

2:11they really resist that decolorization.

2:14And because they resist decolorization

2:16with what's called your acid-fast kind

2:19of like staining, which is again we use

2:21acid alcohol, they don't get that red

2:24color out. They remain kind of a Well,

2:26actually, they kind of retain this

2:28reddish color with a bluish background.

2:30And so, mycolic acids make these

2:33bacteria what we call acid-fast.

2:36All right? So, let's write that down.

2:38This makes it a acid-

2:41fast bacteria.

2:44And this is going to become pretty

2:45critical cuz when we actually start

2:46getting into um

2:49the actual testing process where we do

2:50something called acid-fast bacillus

2:51smears,

2:52one of the beautiful things about, you

2:54know, generally mycobacterial species is

2:57that when you again go through them, you

2:58give them this kind of reddish, pinkish

2:59dye, you give them an acid alcohol, and

3:02that should wash all of that off. Any

3:04kind of mycobacterial species exhibit a

3:06lot of these mycolic acids, and they

3:07resist that decolorization. So again,

3:09because of that, they stay. What does

3:11this mean when they're acid-fast?

3:13Is they stay red.

3:15So, let's actually write that out here.

3:17They remain

3:20red.

3:22And all that tells me is that there is

3:24the presence of mycobacterial species.

3:26Doesn't tell me if it's TB, it doesn't

3:28tell me if it's like ADM or any of these

3:29other different types. It just tells me,

3:30"Hey, there's a mycobacterium present."

3:32Now,

3:33one of the other really important things

3:34about mycobacterium

3:36is not only just its cell wall, which is

3:38rich in these mycolic acids. Mycolic

3:40acids makes it pretty, pretty hardy type

3:41of pathogen, but also it's got other

3:43unique characteristics. Naturally, what

3:45we look at with these bacteria is

3:47something called their doubling time.

3:49And we look at this logarithmic scale,

3:50which looks at time on the x-axis and

3:52logarithmic number of cells on the

3:54y-axis. And generally, bacteria have

3:57this type of growth pattern. What we

3:59notice about Mycobacterium tuberculosis

4:02is it has a very very long

4:05doubling time, or it has a very

4:07prolonged takes a really long time for

4:09this thing to grow. So, it has a very

4:11long

4:14doubling time, which means it has a slow

4:15growth process.

4:17One of the downsides about this is that

4:21well, there's two things. One is

4:22whenever you try to do cultures to

4:24actually see if you can grow this type

4:26of particular bacteria,

4:28it takes a really long time. So, often

4:30times when we try to do cultures for

4:31these patients, the clinical application

4:34is that it takes

4:36sometimes two sometimes like 6 weeks

4:42for cultures to grow out.

4:46And that's kind of one of the potential

4:48downsides.

4:49And so, that's kind of a clinical

4:51application of their really really long

4:53doubling time. It's since it takes super

4:55super long for these things to grow,

4:57when you try to culture these things, it

4:59just takes a really really really long

5:01time. But, these are the gold standard.

5:03Another thing about tuberculosis is it's

5:06it's predilection. So,

5:08Mycobacterium tuberculosis is what's

5:09called an obligate aerobe. All right?

5:12So, let's write that down. So, it has a

5:13long doubling time, but it has an it's

5:15an obligate

5:17aerobe, which means it really really

5:19needs and it really prefers

5:22to be in high levels of oxygen tension.

5:25If you look at the lungs, and we kind of

5:27imagine here for the lungs,

5:29all right? Here we have the different

5:31parts of the lungs. You have your upper

5:32lobes, you have your middle lobe just

5:34here on the right side, and then you

5:35have your lower lobes. Which of the

5:37lobes has the highest oxygen tension?

5:40It's generally the upper lobes. And so,

5:42what happens is mycobacterial species,

5:45not only do they have a very long time

5:47period we start off with this bacteria

5:49and then we double it, right? But also

5:53they prefer the upper lobes cuz that's

5:55where the highest oxygen tension is

5:58present. So one of the other things

5:59about this is because it's an obligate

6:01aerobe it has a preference

6:06for

6:08the apex of the lungs.

6:11Because of why? That has the highest

6:13oxygen

6:14tension.

6:16So that's going to be where it wants to

6:17live. It wants to be in those areas

6:20where there's going to be a lot of

6:21oxygen. All right. So so far we got

6:24Mycobacterium tuberculosis. One of the

6:25most important things about it with

6:28respect to its overall structure is the

6:29mycolic acid residues. Makes it pretty

6:31hardy. Also

6:33makes it really unique that whenever you

6:36take mycobacterial species and you

6:38undergo decolorization and then you try

6:41to again give them this new counter

6:43stain they don't take that up. They

6:45remain that reddish color. Again, they

6:48have a really long doubling time which

6:49kind of sucks when you got to culture

6:50these patients cuz it means it's going

6:52to take a while for you to actually get

6:53these to grow out. That also means that

6:55you got to put these patients on

6:56antibiotics for a really long time as

6:57well. So there's actually another

6:59component to that. It's an obligate

7:00aerobe. Prefers which areas of the

7:03lungs? It prefers the apex of the lungs

7:07because of the high oxygen tension.

7:09There's a third component to these that

7:10makes them really scary. The other

7:12component is that they have a lot of

7:13what's called virulence

7:16factors. All these mean is that

7:19essentially the mycobacterium have

7:21really nasty kinds of weapons that make

7:24it able to evade the immune system and

7:26make it really hard for the immune

7:28system to try to be able to kill these

7:29species. So what are these? Well,

7:32one of them

7:34is here in this S. So it's called a

7:36sulfatide.

7:38So let's say here you have a macrophage,

7:40right? Here's our macrophage. And this

7:42macrophage, generally what it wants to

7:44undergo

7:46is it wants to undergo a process

7:48>> [clears throat and cough]

7:49>> called uh making a phagosome. So, in

7:51other words, what happens is let's say

7:53you take this Mycobacterium species up.

7:56It undergoes phagocytosis. So, what does

7:58that mean? It takes it from the outside,

8:00which is out here,

8:02engulfs it, and brings it inside. That's

8:03called a phagosome. And the process by

8:06which we go to do this is called

8:09phagocytosis.

8:10Then, it wants to uh fuse with this

8:13little green structure. What's that

8:14called? A lysosome. So, then we should

8:17make

8:19a phagolysosome,

8:21which is the fusion of the phagosome

8:23and the lysosome.

8:25And what happens is the purpose of doing

8:27this is that you take all of these

8:29really nasty, harsh lysosomal enzymes,

8:33and you mix it with the phagosome that

8:35contains the bacteria. And the goal is

8:37to do what? Is to cause killing, right?

8:41It's to basically kill

8:44the Mycobacterium tuberculosis. We'll

8:46put MTB.

8:48That's the goal is to kill the

8:49Mycobacterium tuberculosis by using this

8:52phagolysosome.

8:54Well,

8:55what happens is it has this thing inside

8:57of it, and it's called a sulfatide. So,

9:00again, what is it going to be over here?

9:01It has something called a sulfatide.

9:05And sulfatide is essentially the

9:06virulence factor that inhibits

9:11So, they have the presence of this thing

9:12called a sulfatide. And the sulfatide

9:14inhibits at what point in this process?

9:17It inhibits the fusion of the phagosome

9:20and the lysosome. So, you don't get this

9:22process. Therefore, you can't have a

9:24really easy time killing the

9:26Mycobacterium tuberculosis. And so, this

9:28becomes more challenging. You see how

9:30that pretty much allows them to

9:32essentially kind of evade the immune

9:34system? Another thing is

9:36when you have just a couple of these by

9:38themselves, right? You just got one dude

9:41just hanging around and it's by itself.

9:42It's it's more susceptible to getting

9:44jacked up. So, because of that, what

9:47these things do is they carry this kind

9:49of molecule on them. And this is called

9:52cord factor. And cord factor is

9:55essentially kind of like a glue. That's

9:57the way I want you guys to think about

9:58it. It's like a glue.

10:00And essentially what it does is it does

10:01two things. One is it really helps to

10:03enhance your macrophage involvement. And

10:06it also helps to really inhibit

10:08neutrophils. But one of the biggest

10:10things about this cord factor is it

10:12really causes what's called serpentine

10:15kind of growth

10:16or serpentine formation is what I want

10:18you to remember. So, it causes

10:20serpentine

10:23formation or serpentine cords

10:26of the Mycobacterium tuberculosis. So,

10:29essentially this thing acts like a

10:31little glue between

10:34these guys. And then they can grow

10:38and almost give you like this Well, if

10:40you kind of think about it, it's maybe a

10:42little bit of a stretch with my drawing,

10:44but the serpentine cord, which is all of

10:46these mycobacterial species kind of

10:48linked together. It's really hard for a

10:50macrophage to be able to defend against

10:52this. All right? As compared to just one

10:55of these by themselves. So, it's a whole

10:57group of friends taking on this kind of

10:59like macrophage versus just one or two

11:02of them by themselves.

11:03All right? So, that's kind of the

11:05benefit of this is that it just makes it

11:06harder for the macrophages to fight

11:07against them. So,

11:10what we get out of this is that

11:11Mycobacterium tuberculosis is a pretty

11:13It's a pretty tough dude, all right? It

11:14has the capability of having mycolic

11:17acids, which makes it kind of resistant,

11:19all right? But also it also really makes

11:21it kind of interesting with very unique

11:23features when it comes to diagnosis.

11:25We know [clears throat] about some very

11:28unique characteristics of it. One is it

11:30takes a long time for it to be able to

11:32grow. And because of that, there's two

11:34downsides. One is it takes a long time

11:36for us to get cultures, and it also

11:38takes a long time for us to completely

11:39clear the infection. So, we should

11:41actually write that down. So, there's

11:42actually two components here. One

11:44>> [clears throat]

11:45>> is it takes time for it to grow, and the

11:47other one is it takes time for the for

11:49the infection to clear with antibiotics.

11:52Takes time

11:55to clear

11:58the Mycobacterium tuberculosis with

12:01antibiotics. You'll see whenever we get

12:03to the actual treatment section, people

12:05have to be on these antibiotics for

12:06sometimes 3 months, 6 months, 9 months.

12:09It really depends. That's an insanely

12:10long time, and it probably has something

12:12to do with that long doubling time.

12:14All right? We know it prefers the upper

12:16lobes of the lung. That's going to come

12:17in really, really critical when we talk

12:18about what's called reactivation TB. And

12:20also, one of the big, big things here is

12:22this thing is pretty hardy. Besides the

12:24mycolic acids, it has these things

12:26called sulfatides and cord factor, which

12:28basically allow for it to kind of become

12:31more hardy and make it harder for the

12:33immune system of the host to fight

12:35against it. Now,

12:37we know the pathogen that basically can

12:40cause this problem. The question is is

12:42how do we get it, and how does it

12:44actually cause a disease? Because you

12:46don't hear about Mycobacterium

12:47tuberculosis like a ton. Well, one of

12:50the big things is exposure.

12:52When we talk about risk factors for

12:53exposure, it's really

12:56how you

12:57>> [clears throat]

12:57>> I would say how you get the bacteria.

12:59And so, so this is basically how you get

13:04the bacteria

13:07into the lungs. That's really what it

13:09comes down to. It's how you get the

13:10bacteria.

13:11Now, when [clears throat] we talk about

13:13this,

13:15how do you how do you actually get it?

13:16Well, it's via respiratory droplets. And

13:18so, whenever a person is nearby somebody

13:21else who has maybe Mycobacterium

13:23tuberculosis,

13:25and they cough, they sneeze, and that

13:28respiratory droplets move into the

13:31lungs. They find an opportunity to get

13:33down here and start causing some

13:35potential damage if the person's immune

13:38system,

13:39for whatever reason, doesn't have the

13:41capability of being able to fight back.

13:42So, how this thing gets in is via the

13:44process that's called respiratory

13:46droplets. So, you have to be relatively

13:48close to someone who probably has TB

13:51or has a very high risk,

13:54you know, a scenario of potentially

13:56having TB. So, we're spreading this bad

13:59boy via respiratory droplets.

14:02How would I actually really increase my

14:03risk of getting the bacteria? Well, one

14:06is high prevalent areas. So, I would

14:08call this more specifically endemic

14:12exposure.

14:13That's really what it comes down to.

14:15It's endemic exposure. So, what areas

14:17that have a high kind of prevalence of

14:19tuberculosis? Asia, Africa,

14:23probably even like Latin America as well

14:26if we wanted to add that one in there as

14:27well. So, here, we'll actually we'll

14:28throw that one in there, too. Latin

14:30America. So, again, it's more

14:31particularly those who were kind of born

14:33into these particular areas or traveled

14:35to those areas. That's an exposure risk.

14:37The other thing is going to be some type

14:38of like close contact exposure. Um and

14:42so, what do I mean by this? This is

14:43could be a family member, this could be

14:45a friend, but it's someone who you were

14:47around and they had active TB. This is a

14:49pretty high risk component. So, again,

14:52endemic exposure really, really

14:53important especially for your exams. Um

14:55but I'd say the close contact one is

14:58just anybody. This doesn't really

14:59matter, but this is like again, it is

15:01the most likely one to have that highest

15:04risk of kind of inoculation. So, close

15:06contact exposure with someone, again, it

15:08has to be it's someone who has active

15:10TB. All right.

15:12The other component here is going to be

15:15probably higher risk kind of areas. Um

15:20and so, what do I mean by this? The last

15:22one I would say is just going to be kind

15:24of like overall high-risk regions or

15:26high-risk kind of like workplaces,

15:29facilities. So, high-risk areas.

15:33Um, and so the ones that I would want

15:35you guys to think about for this one is

15:37probably going to be like the hospital.

15:39So, anybody who's in the healthcare kind

15:41of like aspect, probably going to is

15:43going to have some degree of risk here.

15:45So, healthcare would probably be a big

15:47one. Um, another one I [clears throat]

15:49would definitely want to think about is

15:51potentially like homeless shelters. That

15:53is a potential risk factor as well. So,

15:55the homeless shelters.

15:57And [snorts] we could even go down the

15:58line. Sometimes they even include in

16:00like prisons. If you really want we

16:02could even add in like prisons as well.

16:04But, I think the biggest ones that I

16:06would want you guys to remember

16:08is probably going to be a close contact

16:10exposure or some type of like especially

16:12for the exams cuz it's a perfect

16:14vignette to set you up. They just came

16:15back from traveling or they were born in

16:17an some area of Asia, Africa. So, they

16:19had that exposure risk. All right. So,

16:21the first thing is they get the bacteria

16:23The second component is we have to then

16:25determine, okay,

16:26is a person they got the bacteria in,

16:30are they having a primary infection

16:34that progresses, right? That progresses.

16:39Or are they having a primary infection

16:44that goes dormant?

16:48And then in certain scenarios, it

16:52reactivates.

16:55And that's really kind of the step here

16:57that's critical. So, you have a person

17:00who gets a primary infection. Either

17:01they progress and they continue to have

17:04active disease or they get a primary

17:06infection, it goes dormant, and then it

17:08reactivates. So, let me explain

17:10something for a second. In most

17:12patients, I'd probably say greater than

17:15greater than or equal to 90% of cases,

17:18they go to a stage called latent.

17:21So, in other words, this means that they

17:23have latent TB. Latent TB means that

17:25they don't really have an active

17:27infection. What kind of happens here in

17:29just a simplistic way, cuz I'm going to

17:31go into detail more there in a second,

17:33is they get the bacteria in. So, here's

17:35the bacteria.

17:37Then what happens is

17:38if you have a good enough immune system,

17:41your immune system's capable, it's

17:42functioning in the normal individual,

17:44you'll wall this thing off. And when you

17:46wall it off, it kind of goes into this

17:48dormant state, where it's still there.

17:50It's still there. It's actually present

17:53in your lungs. You maybe didn't

17:54completely eradicate it. But you walled

17:56it off. And so, it's in this sleepy

17:58state. That's called latent TB.

18:01In about probably whatever the remaining

18:03portion of this is, so less than 10% of

18:06cases, they can progress. So, in other

18:09words,

18:10you get this kind of infection, the

18:12pathogens get here,

18:14maybe you try your best to kind of wall

18:17it off, but it doesn't really do a great

18:18job because your immune system isn't

18:20strong. And because of that, it spreads

18:22to a bunch of different areas. And maybe

18:24it spreads throughout the lungs. Maybe

18:26this even gets into the bloodstream. It

18:29gets into your lymphatics, and this

18:30thing starts to kind of go haywire

18:32because you just don't have maybe that

18:34proper immune system to wall this thing

18:36off. And so, because of that, this thing

18:39spread throughout the lungs, or it

18:42spread to the bloodstream, and it became

18:44disseminated.

18:45In this scenario, we call this

18:48primary progressive TB.

18:51So, primary progressive

18:55TB.

18:56All right? So, that is the first thing

18:58that I want you guys to remember is,

19:00again, most of the patients, if they

19:02have a good enough immune system, they

19:04go into a state of dormancy. Some of

19:06those patients who just don't have a

19:07robust immune system, they're probably

19:08somewhat immunosuppressed,

19:10and we'll get into that. They can't kind

19:12of wall this bacteria off. And so

19:14because of that it can kind of spread

19:16spread spread even get into the

19:17bloodstream and start to disseminate.

19:19>> [gasps]

19:19>> And another scenario out of this

19:21patients that most often go into latency

19:24in certain scenarios, sometimes you have

19:28something that pushes the individual to

19:31where they had it walled off, but then

19:33what happened is

19:35is it decided to maybe come out of

19:37dormancy. And I'll get into how this

19:39actually happens, but whenever they're

19:41in these areas, especially reactivation,

19:45reactivation typically likes to occur in

19:48the upper lobes of the lungs. Why?

19:50Remember I told you

19:52that this is an area of high oxygen

19:54tension.

19:55And so what we'll notice in patients who

19:57get reactivation TB is they end up

19:59getting kind of this liquefactive

20:01necrosis

20:03that occurs in the apex of the lungs.

20:06And that my friend is called

20:07reactivation TB. All right, so this is

20:10called reactivation.

20:13Some even call it post-primary. So

20:15reactivation TB or post-primary TB in

20:17case you hear that. So,

20:20what I want you to get at is you get

20:21exposure to the bacteria, gets its way

20:23into the lungs. If it gets into the

20:25lungs, it can either do one of two

20:27things. It can progress if you just

20:28don't have the robust immune system or

20:30you can go into a dormant state. But in

20:32certain scenarios,

20:34you can reactivate it. The question

20:37becomes not as much here, it can be a

20:40certain degree of a question, but I'd

20:41say a lot of it comes in here.

20:43What's really

20:45the reason why they come out of latency

20:47and go into this reactivation state?

20:49And often times it comes down to a

20:51suppressed immune system. So one of them

20:54is that you have a really diminished

20:56activity

20:58and I promise you'll see what I mean by

20:59this a little bit later is you have a

21:01reduced activity of your T-cells. And

21:03particularly it's called your TH cells.

21:05Your Technically, these T helper cells

21:08are CD4 cells. That's really what we're

21:10going to call them. They're CD4 cells.

21:13And what is really really critical about

21:16our CD4 cells, which we're going to

21:17represent here, is that they help to

21:19secrete a bunch of different types of

21:20cytokines that are really helpful for

21:22this TB.

21:23One that they release is really

21:25critical. And what it does is it really

21:27kind of activates macrophages, makes

21:29them really really just beasties, and

21:31try to try to really focus on killing

21:33and destroying these mycobacteria. Makes

21:35them a little bit more hardy. All right?

21:37That chemical that they release is

21:40called interferon gamma. All right?

21:44Interferon gamma activates macrophages.

21:47And then what macrophages do is they

21:49also pump out a particular cytokine to

21:52activate more T cells, bring in more

21:54macrophages. And that's called TNF

21:56alpha. But TNF alpha is not only

21:59released

22:00by, in this case, the macrophage, it's

22:02also released by

22:05these T cells.

22:07And what happens is in all of this is

22:08that T cells really really, whenever

22:11they get hit with interferon gamma,

22:13it activates macrophages. Macrophages

22:15release TNF alpha. T cells release TNF

22:17alpha. What does this do? Brings more

22:19macrophages to the area.

22:22All this is trying to do is is if I

22:24bring all of these immune system cells

22:26to the area,

22:27theoretically, I should be strong enough

22:30to take this bacteria and push it into

22:34the jail.

22:35Put it into the prison. And I'll explain

22:37what that prison is over in the

22:39pathophysiology. But for right now, what

22:40I want you to trust about this is that

22:43really what we're trying to make is this

22:44this prison is what we're going to refer

22:46to as a granuloma for right now. So, for

22:48right now, I just want you to trust me

22:49that this is what we're going to

22:50eventually push them into is a

22:53granuloma. All right? But we need

22:56sufficient amount of T cells, and we

22:57need sufficient amount of these like

22:59inflammatory cytokines.

23:01So, what if I don't have T and what if I

23:03have a reduction

23:05>> [clears throat]

23:06>> in these cytokines?

23:08And the inflammatory cytokines, I'd say

23:10the most important one

23:12>> [clears throat]

23:14>> is going to be what?

23:15Well, it definitely is interferon gamma,

23:17but I'd say TNF alpha

23:19is probably going to be the biggest one

23:21that I want you guys to associate with

23:22this.

23:23So, [clears throat]

23:24what conditions

23:26really reduces your T-cells? Come on,

23:28think about it.

23:29If I have a condition called

23:32HIV

23:34or AIDS, what does that do to my T-cell

23:36levels? It drops them.

23:38So, in patients who have HIV AIDS, you

23:40drop their T-cell levels. If you drop

23:42[clears throat] their T-cell levels,

23:44they don't make as much of the

23:46interferon gamma. Can they stimulate the

23:48macrophages? No.

23:50If they can't, they inhibit the

23:51macrophages. Do they release TNF alpha?

23:53No. Because of that, do you put them

23:55into the prison? No.

23:57And so, what ends up happening is,

23:59unfortunately, these little suckers

24:00escape

24:02and they grow and they grow and they

24:03grow and they grow.

24:05And this is basically what pushes the

24:06bacteria

24:09to grow

24:11and cause more damage.

24:13And that's what we don't want, right?

24:14So, after this, you're getting more of

24:16this bacterial growth.

24:18If I have patients who have really,

24:20really low levels of these cytokines,

24:22what would be a reason for this

24:23happening? Well, I think the biggest one

24:26is any kind of immunosuppressant.

24:28That's really the case. Is any

24:30immunosuppressant drug is probably going

24:32to be a pretty strong trigger here. So,

24:34we'll write this one out. So, this is

24:35really any kind of

24:37immuno-

24:38suppressants.

24:41And again, I'll give you guys a couple

24:42examples of these, but I think the most

24:44common one that I would want you guys to

24:46think about for the exam

24:48is what type of drug?

24:50>> [clears throat]

24:50>> A TNF alpha inhibitor.

24:52So, steroids, transplant rejection meds,

24:56TNF alpha inhibitors, which we use in a

24:58lot of different types of conditions,

24:59especially things like inflammatory

25:01bowel disease. And we use it in a lot of

25:03like rheumatic diseases. So, these are

25:06These are things that we really want to

25:07consider. If you drive down their kind

25:10of overall immune response, you don't

25:11keep them in these granulomas.

25:14And so, if we can't keep them in the

25:15granulomas, either they progress,

25:18right? That's one of the other concept

25:19here is that again, same It's kind of a

25:21similar concept here. They don't put

25:23them in the granulomas,

25:25or they don't maintain the granulomas.

25:28They break free. And when they break

25:30free, their predilection

25:33is for what area?

25:34To the apex of the lungs.

25:36And then for the primary progressive,

25:38it's usually middle and lower lobe,

25:39which I promise we'll get into.

25:41So again, what I want you to understand

25:43here is when a person gets exposed to

25:44something like Mycobacterium

25:45tuberculosis, the exposure is getting

25:47the bacteria in.

25:49The reason why it even becomes active,

25:52which is either primary progressive or

25:53reactivation,

25:55is you have to have something that's

25:57suppressing the immune response. HIV

26:00AIDS dropping your T cells, or

26:02immunosuppressants shutting down the

26:03cytokine response.

26:05That could be steroids, that could be

26:06transplant rejection meds, that could

26:08even be TNF alpha inhibitors. HIV AIDS

26:10is probably going to be one of the

26:11highest risk, probably about 50-fold

26:13increased risk in tuberculosis with HIV

26:16AIDS. All right? That's the big thing.

26:17Now, if you have a good immune system,

26:19you're going to probably be fine, and

26:21you're going to go into a dormancy

26:22state, and you don't have to potentially

26:23worry about this. And now, these are the

26:25biggest risk fa- These are the biggest

26:27risk factors for why this happens, but

26:29it could be a lot of other mild ones. I

26:31just wanted to give you the most

26:32probably extreme ones, but you can see

26:34this in patients who just have

26:36We can see this in patients who are just

26:37malnourished, acutely ill, periods of

26:39just overall physical stress. This can

26:40also drive this process.

26:42All right. So, with that being said,

26:45we talked about the particular pathogen,

26:48which is Mycobacterium tuberculosis. We

26:50talked a lot about the risk factors for

26:53getting exposed and we talked about the

26:54risk factors that actually cause it to

26:55progress.

26:57What I need to do now, which is going to

26:59take a little bit of time, but I want

27:01you guys to stick with me, is to go

27:03through once the moment this

27:04mycobacterium hits the alveoli,

27:07how does it cause these granulomas?

27:10Which is going to be a you know, a hefty

27:11discussion, but let's kind of dig into

27:13it. All right, so first thing is how do

27:14they spread again?

27:16Respiratory droplets.

27:18So, there is some type of movement of

27:21these pathogens.

27:23And basically,

27:25they are going to be spread via

27:28respiratory droplets from a close

27:29contact exposure, from being in an

27:31endemic population, from being in a high

27:34risk area. Either way, these things make

27:36their way

27:38into the lungs. I told you a little bit

27:41about what's the most common locations.

27:44I'm going to recap that again.

27:45Oftentimes these prefer to start off

27:48their initial infectious kind of process

27:51really in the lower lobes

27:55and in the middle lobes.

27:57And again, it could be the right or the

27:58left, but again, usually there's only a

28:00middle lobe on the right, all right?

28:01[laughter]

28:02But it could be it's usually more in the

28:03middle, lower lobes. So, that's the

28:05first thing that I want you to remember

28:07is initial location is often times it's

28:09going to be middle lobes or lower lobes.

28:11But there's another component that I

28:13have to add on to that.

28:15So, first thing is often times the

28:17initial location where it's going to

28:18start all of its kind of process is

28:20middle

28:21or lower lobes.

28:25But the other thing is look how close it

28:27is to this pink tissue that I'm going to

28:28draw here.

28:29So, we have a piece of kind of a pink

28:31tissue here. This is the visceral

28:33pleura.

28:35And then what's this one here called?

28:36That's called the parietal pleura.

28:38It's just beneath the visceral pleura.

28:41So, we call that a subplural

28:44type of location, right? So, it's middle

28:46lower lobe, and it's usually sub

28:49plural.

28:51All right.

28:52We have a location of where these

28:54initially start once you get it

28:56exposure.

28:58Now, once they get in there, guess what?

29:01Macrophages say,

29:03"Hold my beer. I got you. I'm going to

29:05help you out a little bit here, buddy."

29:06So, what happens is the macrophages are

29:08going to be a part of your innate immune

29:09response.

29:10And what they're going to do is is

29:12they're going to see these

29:13mycobacterium, and they're going to

29:15undergo a process, which I told you

29:17guys, which is going to be where they

29:19eat them. They undergo the eating of

29:20them. They bring them inside of them.

29:23And what's that called? This is called

29:25phagocytosis.

29:27So, the first step is going to be

29:28something called phago

29:32cytosis. That's going to take it inside.

29:34It's going to bring it inside of this

29:35little thing called a phagosome, which

29:37is going to be right there. And again,

29:39what's going to be inside of it? It's

29:40going to be the mycobacterium

29:41tuberculosis.

29:43Then, what happens is

29:45this son of a gun, we already told you,

29:47it's supposed to fuse. What is it

29:49supposed to fuse with? Well, then you

29:51have your phagosome,

29:53and it's supposed to combine with

29:55something called a lysosome, right? So,

29:57here's our lysosome.

29:59And this is going to have all the

30:00lysosomal enzymes. This phagosome is

30:03going to contain the mycobacterium

30:04tuberculosis. And what is it supposed to

30:07undergo? It's supposed to undergo

30:09fusion. So, then we should have

30:11something called fusion. So, here we

30:13have again the phagosome,

30:15which is basically the macrophage that

30:17contains the

30:19TB.

30:21Then, after that, we're going to have

30:23fusion of the phagolysosome. Well, we

30:25should have fusion of the phagolysosome.

30:28So, this step we should have

30:30phago

30:33lysosome

30:35fusion.

30:37Which is going to be at this step right

30:38here. So, the first process was

30:41phagocytosis. The second process is

30:43going to be phagolysosome fusion. I told

30:46you that there was something that

30:47happens at this step.

30:49We have something inside of the

30:52mycobacterium species that prevents

30:53this. Do you guys remember what it was

30:55that inhibits this process?

30:57I'll give you a hint. It started with an

30:58S. It was called the

31:00sulfatides.

31:02Yeah, so the mycobacterium has something

31:04called sulfatides. And the sulfatides

31:07are pretty much

31:09a virulence factor that what it's going

31:11to do is it is going to inhibit this

31:14phagolysosome fusion. That's what it's

31:17going to do. So instead of these guys

31:19going and actually fusing together,

31:22what happens? We're going to inhibit

31:24that process. We're going to inhibit

31:26this fusion. And so now what happens is

31:28these were supposed to come together,

31:30but they don't. And so we kind of keep

31:32this, unfortunately, the phagolysosome

31:34never fuses. And so we're still stuck

31:37with

31:38this this guy over here containing all

31:41of that TB. And we're still

31:42unfortunately stuck with this lysosomes

31:44over here which aren't able to fuse.

31:48What happens is

31:49this bacteria, it's not really

31:51undergoing destruction.

31:52So because of that, guess what it

31:54decides to do.

31:55It decides to replicate

31:59in the macrophage.

32:04So that's the next step. So the first

32:06thing was phagocytosis. Second thing is

32:08once we actually have the phagosome is

32:10to fuse it with the phagolysosome. All

32:12right, to actually fuse it with the

32:14lysosome to make a phagolysosome. So

32:16these were supposed to come together.

32:18All right, we're supposed to have the

32:19fusion of these two. And again, it's

32:21going to be the what two things? It's

32:22the phagolysosome

32:25I'll actually put this here. It's

32:26supposed to be the fusion of the

32:28phagosome and the

32:30lysosome. We're supposed to bring these

32:33together, but but not going to. Because

32:36of that, all you end up having here is

32:38just bacteria that are going to

32:40replicate in the macrophage. These

32:42things are going to just replicate like

32:43bunnies.

32:45Because of that, now we get this

32:46infected macrophage. So now I have this

32:49infected macrophage, and what does it

32:51have all the way filled inside of it?

32:54It's got all these

32:56mycobacterium species just growing

32:57within it. So again, what is this here

32:59called? This is called a infected

33:03This is called an infected alveolar

33:07macrophage.

33:09Now, that's the first thing that I want

33:12you guys to remember in this step. So

33:13the first component here that happened

33:16is that you had inhalation via

33:18respiratory droplets, gets into the

33:20airway, causes its initial kind of site

33:22of infection, which is middle lower

33:24lobe. It's usually subpleural.

33:27If you zoom in into the alveoli,

33:29macrophages are supposed to undergo

33:30phagocytosis. That actually does occur.

33:32They get a phagosome. You're supposed to

33:34combine the phagosome and the lysosome

33:36to make a phagolysosome. But guess what

33:38the sulfatide does? The sulfatide

33:40inhibits that fusion. So now that never

33:42happens, and then you just have all of

33:44these bacteria that replicate replicate

33:45in the micro macrophage. Now I got an

33:47infected macrophage. It's incapable of

33:50doing its job.

33:51So what does it need? It's got to call

33:53out on to its friend.

33:56So what happens is

33:57the infected macrophage releases a

33:59couple different cytokines.

34:01It releases things like interleukin 1.

34:04It releases things like TNF

34:06alpha.

34:07And that's going to get pumped out from

34:09this alveoli, which is where all of this

34:10process is occurring. It's going to get

34:12into the blood, or it's going to get

34:14into the lymphatic circulation.

34:16Once it does that, these cytokines are

34:18going to go and activate different types

34:20of immune system cells, right? And

34:23generally the way I want you to think

34:24about them is just overall

34:25antigen-presenting cells. And we're

34:27going to try to activate these

34:28antigen-presenting cells. What are the

34:30two antigen-presenting cells that I

34:31really want you guys to remember in this

34:33scenario?

34:34The two antigen presenting cells is

34:35going to be the dendritic cells. That's

34:38going to be kind of the heavy hitters in

34:39this scenario.

34:41And then again, it's going to be

34:41monocytes that come to the area and

34:43generally turn into

34:44macrophages.

34:46So, these are the two ones that I want

34:47you to think about, but the heavy hitter

34:49in this scenario is going to be the

34:51dendritic cells. So, they're going to

34:52come from the lymph, they're going to

34:53come from the blood, and they're going

34:54to come to this area. All right? So,

34:56we're going to activate those puppies.

34:58And again, who's really helping with it?

35:00It's these high levels of things like

35:02interleukin 1 and tumor necrotic factor

35:04alpha that's being released by the

35:06infected macrophages.

35:08Once that happens, these dendritic

35:10cells, here's our antigen presenting

35:11cell. We're just going to use this. This

35:12is our antigen

35:14presenting cell. All right? Here is the

35:16Mycobacterium tuberculosis.

35:19It undergoes phagocytosis. So, once it

35:22undergoes phagocytosis inside of this

35:25dendritic cell,

35:26basically what happens is it will take

35:28some pieces of it and expose it on its

35:31MHC 2 complex.

35:33When it exposes it on the MHC 2 complex,

35:35you're supposed to have this interaction

35:36here, which is the MHC 2 complex

35:39with your T cell receptor.

35:42These interact. Basically, once you get

35:44this connection, you have generally a

35:47co-stimulatory signal, and this thing is

35:49ready to roll. What's ready to roll?

35:51This is

35:53a naive T cell, which means it doesn't

35:55really it's it's not kind of it doesn't

35:57know what its job is meant to be. It

35:59doesn't know if it's meant to be a T

36:00helper cell, a cytotoxic T cell. It

36:02doesn't even know what kind of T helper

36:04cell it needs to be.

36:05So, what happens is the macrophage is

36:06smart.

36:08And some other cytokines that get

36:09released here is not just interleukin 1

36:12and tumor necrotic factor alpha.

36:14So, let's actually kind of show that

36:15these are the cytokines first.

36:18And then we'll bring these over here.

36:23But, another cytokine that's also

36:25getting kind of pumped out here.

36:28And causes some fatigue

36:30helpful scenarios here is called

36:32interleukin 12. So that's another side

36:35that kind of gets released. So it's

36:36interleukin 1, TNF alpha, and

36:38interleukin 12. Once the dendritic cell

36:41undergoes this phagocytosis, takes a

36:43piece of that mycobacterium and exposes

36:45it on side of its membrane, activates

36:48this interaction,

36:49then interleukin 12 comes in and really

36:52drives this naive T cell to have an

36:54actual determination of what it's going

36:56to be.

36:57And so what it does is it says, "All

36:59right, folks, I know what I'm meant to

37:00be when I grow up."

37:02And it turns into a very specific type

37:04of T cell that undergoes an excessive

37:07amount of proliferation.

37:09And this is called T helper 1 cells.

37:13And that's where these are becoming the

37:15big dogs. The macrophage, it just

37:16couldn't handle the it couldn't handle

37:18the heat. And so what ends up happening

37:20is

37:21with this interaction with the

37:22antigen-presenting cells and the

37:24interleukin 12, this naive T cell, it

37:26became TH1 cells.

37:28TH1 cells, I already told you, they

37:30release a very, very heavy amount of a

37:33very specific type of cytokine. Do you

37:35guys remember what that one is? It's

37:37called interferon gamma.

37:40Interferon gamma is the big cytokine in

37:43this scenario that is going to help us

37:45to drive a particular type of immune

37:48response.

37:49One of those immune responses is it's

37:51going to tell this macrophage

37:53to become better. It says, "Just come

37:56on, bro. Level up your game."

37:58And so the macrophage kind of goes from

38:00being like a phagocytic type of factory

38:02where it kind of eats things to where it

38:04becomes really, really good at releasing

38:06things like reactive oxygen species and

38:08proteases and tries to undergo a lot of

38:10intracellular killing.

38:12All of this is really trying to put this

38:13bacteria into dormancy. So one of the

38:15things that it does is it stimulates a

38:17lot of what's called intracellular

38:19killing by the macrophage. It basically

38:21just makes it like a beast. Makes it a

38:23kind of like a a little bit more of a

38:24enhanced activated macrophage. So, it

38:27goes undergoes intracellular killing.

38:30And that's one thing that it does to

38:31this macrophage is it really, really

38:32amps up its activity to be able to kill

38:34the pathogen.

38:36The other thing here is

38:38is it tells these macrophages to start

38:40to undergo this kind of conversion and

38:43transformation process. And so, it

38:45drives this kind of conversion and

38:47transformation process, if you will,

38:49where a bunch of these macrophages kind

38:51of come together and fuse.

38:53And it becomes one big giant cell.

38:56That's what we call them. We call them

38:57giant cells. So, we actually call them

38:59Langhans giant cells.

39:02So, Langhans giant cells. Some of them

39:04actually make what's called epithelioid

39:05histiocytes, but I don't want you guys

39:07to go too crazy on that. I just want you

39:09to know that what we make is is we

39:11stimulate the formation of these things

39:13called Langhans giant cells. It's

39:15basically, I'm not kidding, just a bunch

39:17of macrophages that are fused together.

39:19And they may contain some of the

39:21mycobacterium tuberculosis in them. And

39:23what else is actually happening,

39:24interferon gamma not only is helping

39:26convert them, but it's making them good

39:28at killing. All of this is supposed to

39:31basically

39:32do two things. One is to help the

39:35macrophages be better at killing the

39:37pathogen and also start to kind of like

39:39wall this off. This big cell becomes

39:42like a wall. It's trying to keep the TB

39:45in one particular place, not letting it

39:47spread around. That's one of the

39:49benefits of this.

39:51So, in this scenario, we started off, we

39:53got the exposure. That thing got into

39:55the lungs. It interacted with the

39:56macrophage. Macrophage couldn't handle

39:58it. Says, let me tell my buddies. Tells

40:00antigen-presenting cells. They come in,

40:03they help with phagocytosing them,

40:04presenting them to naive T cells, and we

40:06turn this into a T helper 1 cell. These

40:08things go ham and start pumping out

40:11interferon gamma.

40:12When they do that, activates the

40:14macrophages, causes them to convert into

40:16big giant cells. We start kind of

40:18killing the pathogen and making a wall.

40:20So, let's talk about what that wall is.

40:23That wall,

40:25if you will, is called a granuloma.

40:28Now, [sighs]

40:28this is what's really interesting. We're

40:30having the granuloma, which we're kind

40:32of just zooming in on here. It's really

40:34in this alveoli. It's Where is it again?

40:36I told you. Usually middle, lower lobe,

40:39and subpleural.

40:42If I zoom in on this and how all of this

40:44is happening in kind of a really cool

40:46sequence.

40:47From the most outer part of this

40:49granuloma is what? Well, the first one

40:52is the orange cells. These are called

40:54your T helper 1 cells.

40:56What are the job of the T helper 1

40:58cells? Well, think about it. This thing

41:00is on the outside and it's just spewing

41:03out what type of cytokine to tell the

41:06Langhans giant cells, to tell the

41:07macrophages to be good at their job.

41:09What is that? Interferon gamma. So, it's

41:12just pumping out

41:13interferon gamma to feed what?

41:17The inner core.

41:19It's feeding the inner core of

41:21macrophages and giant cells. All right.

41:24Then we get into the second component.

41:26What's that? Well, technically it's

41:28going to be the kind of the outer wall,

41:30which is all those macrophages that fuse

41:32together. Some of them are epithelioid

41:34histiocytes and a lot of them are

41:36Langhans giant cells. So, that's the

41:38second part here.

41:40As the Langhans

41:43giant cells. And again, I would even add

41:45in there, if you guys want, that these

41:47are also going to contain the

41:49epithelioid histiocytes. These are

41:51basically

41:52a bump. Basically, I'd say a group

41:56of macrophages

41:59that are fused.

42:02And they're kind of helping to contain

42:04some of this pathogen. That's really

42:05their job. It's a bunch of them that

42:07help to contain the particular pathogen.

42:09And then the inner kind of core is the

42:12macrophages. Now, some of these

42:15obviously could be infected. Some of

42:16them may not be infected. So, but again,

42:18I think the important thing is that a

42:20lot of these are the ones that are

42:21really undergoing a lot of the killing

42:23process. And some of them will contain

42:25the pathogen inside of them. And even

42:27some of the Langhans giant cells may

42:28contain some of the pathogen inside of

42:30them. But the big component here is that

42:32we're containing it in this outer rim of

42:35T cells. So again, macrophages are cool

42:38because they're supposed to do two

42:39things in this scenario. One is they're

42:41supposed to kill, but they're also

42:44they're really important to maintain

42:46this granuloma.

42:48And so they do two things. One is they

42:49kill

42:51the Mycobacterium tuberculosis. The

42:53second thing is that they really pump

42:55out tons of something called TNF alpha.

42:59So, that's another really, really

43:01important thing that I want you guys to

43:02understand. We made the granuloma, which

43:05was

43:06the macrophage phagocytosed the

43:08Mycobacterium. Couldn't really kill it.

43:11Told T cells, "Hey T cells, I need the T

43:13helper one cells to come over here." T

43:15helper one cells come over. They

43:17activate the macrophages, make them

43:18better eating more of them. Then they

43:20have some of the macrophage turned into

43:21giant cells and come around them. And

43:24then we end up with this kind of like

43:25nice little circular structure here

43:27that's containing a bunch of different

43:28types of cells.

43:30Now, interferon gamma is keeping the

43:32wall in place. Tumor necrotic factor

43:34alpha is really, really critical though.

43:36I'll explain why.

43:38The tumor necrotic factor alpha, there's

43:40there's released from Well, actually,

43:42here, let's just let's zoom in it from

43:43outside here. When we take these cells

43:46here, the T cells, they do also release

43:49TNF alpha, but the macrophages

43:52are really that heavy source of TNF

43:54alpha.

43:55And so what happens is the TNF alpha is

43:57really cool

43:59because what it's trying to do is to

44:01keep more

44:03monocytes, right? Which will come to the

44:06area and turn into macrophages to keep

44:08the lymphocytes coming to the area and

44:10keep reinforcing that granuloma. So,

44:13these are supposed to do that. They're

44:15supposed to pump out things like TNF

44:17alpha to help to stimulate the

44:19macrophages to come to the area. To help

44:21to stimulate the T cells to come to the

44:23area. Right? That's what we want. And

44:25because if they come to the area, we're

44:26going to reinforce and maintain the

44:29granuloma. I told you

44:32if you give someone TNF alpha

44:33inhibitors, you shut down that TNF

44:35alpha. TNF alpha is really critical for

44:38maintaining the granuloma.

44:40These T cells around the outer core are

44:43keeping the granuloma also in place with

44:46interferon gamma. So, the maintenance of

44:49the granuloma is really primarily

44:50maintained by TNF alpha and T cells

44:53secreting interferon gamma to keep the

44:55macrophages intact.

44:57All right. What happens is when you have

45:00all of these cells clumped up together

45:02is oxygen requirements go up. So, your

45:05tissue starts to become hypoxic. So, the

45:07center core

45:09center of the granuloma

45:14experiences undergoes

45:16hypoxia.

45:18That's one event that actually starts to

45:20take place. There's a bunch of different

45:22cells here. A lot of cells. Not enough

45:25oxygen to go around. And so, the most

45:27susceptible area, which is the center

45:29portion of it, undergoes hypoxia. That's

45:31one component here.

45:33All right? The second component here

45:36is that

45:37the macrophages, they are releasing tons

45:40of reactive oxygen species, tons of

45:43proteases. So, there's going to be lots

45:45of reactive oxygen species and proteases

45:47that are released by the macrophages in

45:49attempt to kill the mycobacterium.

45:52Right? And so, there's lots of reactive

45:54oxygen species, lots of proteases.

45:56And what that is designed to do is to

45:59kill the mycobacterium. But this stuff

46:02isn't selective. It says, "I'll damage

46:04whatever I have around me."

46:06And what it does is is since you have

46:08hypoxia to the center and all these

46:10reactive oxygen species, it causes

46:12tissue necrosis in the center. And so

46:15the combination of these things lead to

46:18a tissue necrosis in the center.

46:21And that tissue necrosis starts to kind

46:23of look like it has it's like look like

46:25a bunch of cheese like with holes in it

46:27like Swiss cheese and we call this

46:29caseous necrosis.

46:31So it's technically called caseous

46:34necrosis.

46:36And when that happens, all of the

46:37center, which will represent we'll do it

46:39here. We'll just do it in this kind of

46:41um

46:42Let's just use the black actually. All

46:44of this all of this is the caseous core.

46:47That is going to be the inner center

46:49gooey portion that contains all of that

46:52dead tissue. All right? That's the

46:54tissue necrosis. So what we give this

46:57kind of thing is it's technically a

46:58granuloma but it's got a necrotic

47:01[snorts] caseous core. So what do we

47:03call this thing? Technically this thing

47:05is called a

47:06caseating

47:08It's called a caseating

47:11granuloma.

47:14And And again, if somebody were to say,

47:16"Hey Zach, what's a what's a granuloma

47:17again?" It's an outer core of T cells.

47:20Technically this would be your T helper

47:221 cells. Then you're going to have your

47:23Langhans giant cells. Then you're going

47:25to have your macrophages, right?

47:28And again, in the inner center of it,

47:29you're going to have some necrotic

47:30debris. Why? Because a bunch of the

47:32cells in the center start to undergo

47:34hypoxia because there's too much cells

47:35not enough oxygen delivery. And on top

47:37of that, reactive oxygen species and

47:39proteases that are being released by

47:43macrophages

47:45cause a lot of innocent bystander

47:47destruction. And all of that inner

47:49destructive tissue Actually, we'll do a

47:51different color. Let's do

47:54for right now

47:55let's do kind of a pinkish color for

47:58right now.

47:59Because all of the pink I want to

48:01represent like dead cells. This is like

48:03dead macrophages.

48:05This could be some dead

48:07Langhans giant cells. But what's in the

48:09inner center of it?

48:11The the actual mycobacterium. That's

48:12kind of in this cheesy center.

48:15That is really the inner center goo,

48:17which is going to be containing dead

48:18cells, inflammatory exudate, and the

48:21mycobacterial species.

48:23But the beautiful thing about a

48:24caseating granuloma is I want you to

48:27think about this as the TB prison.

48:29This is essentially going to be my TB

48:32prison.

48:33And if I have a proper immune system, I

48:35should be able to contain these things

48:37in that middle lower lobe portion of the

48:39lung just beneath the pleura.

48:41If I don't have the immune system

48:43capable, it could then progress. If it

48:45goes into latency, it could potentially

48:47reactivate. So now,

48:50let's go into the next step here. The

48:51next component is

48:53we've done a pretty good job at forming

48:55these caseating granulomas.

48:58And again, it's really important to

48:59remember where is this? So what's this

49:01portion here? I'm just going to use the

49:03outer

49:04portion of the lung. We're going to call

49:06this the subpleural portion.

49:08And it's going to be in the middle lower

49:09lobe. And again, it's going to have that

49:12outer core, which is the

49:15T cells, and it's going to have that

49:17inner kind of portion with the Langhans

49:19giant cells, and it's going to have all

49:21this caseous necrotic material. There's

49:23our caseating granuloma, right? Here's

49:26the thing.

49:27There's all these lymph nodes that are

49:29in the hilum. This is connected, dude.

49:31So you got to remember there's there's

49:33lymphatic system channels that exist

49:36here.

49:37And this can drain

49:39into this lymph node.

49:40And so all of these mycobacterial

49:42species, they had the opportunity to

49:43potentially spread over here and cause

49:45that same kind of concept over here in

49:47the hilar lymph nodes.

49:49And so whenever they do that, you get

49:50the same thing, which will have the

49:52outer T cell core.

49:55Then you'll have the Langhans giant

49:57cells.

49:59And you'll have some macrophages, but a

50:00lot of dead cellular debris containing

50:03the mycobacterium. All right?

50:06Now,

50:07when this happens, you have two

50:08components here.

50:09One is you have the caseating granuloma

50:12at this portion of the lung.

50:14And you have a caseating granuloma here

50:17at the lymph node. These are two

50:19different components here. So, the first

50:21thing is we have something called a Ghon

50:23focus.

50:25So, what is a Ghon focus? The Ghon focus

50:26is one. That's basically a caseating

50:29granuloma that is usually near the

50:31middle lower lobe of the lung, and it's

50:33a subpleural structure. So, that's the

50:36first thing. That's going to be this

50:37part. All right? The second one is the

50:40hilar lymph node. So, you have caseating

50:42granulomas that form within the hilar

50:43lymph node and makes it bigger.

50:45And so, that causes hilar

50:49lymphadenopathy.

50:51Now, the combination

50:55of these two gives you something

50:58called

51:01a

51:02Ghon complex.

51:06That is the next component here.

51:08So, we have a Ghon complex.

51:11So, a Ghon complex is essentially a Ghon

51:13focus, which is a caseating granuloma at

51:16the subpleural portion of the middle

51:17lower lobes of the lungs, and hilar

51:19lymphadenopathy, which is due to

51:21caseating granulomas within the hilar

51:22lymph node. That's a Ghon complex. Now,

51:25a Ghon complex

51:28can pretty much You're at this point,

51:30these bacteria are pretty much dormant.

51:33They're kind of in a sleepy state.

51:35They're not killed, they're still there.

51:38What happens though is that we try to

51:40show that this area of the lung healed.

51:43And when it does that, it kind of

51:45undergoes some fibrosis.

51:47And we call this when it undergoes

51:49fibrosis and calcification of the Ghon

51:51complex, we call that a Ranke

51:54complex.

51:56So, what is a Ranke complex? It's

51:57essentially I mean, honestly, the

51:59simplest way of defining this is

52:01essentially this is a

52:03fibrocalcification process. That's all

52:06it is. It's that the Ghon complex

52:07undergoes fibro

52:11calcification.

52:16So, let's example that.

52:17Here,

52:18we're going to have the Ghon focus.

52:21Here, we'll have a

52:22caseating granuloma right there.

52:24Again, T cells, outer core, Langhans

52:27giant cells.

52:28And then,

52:29the inner kind of portion which contains

52:31all of that dead cheesy necrotic

52:32material is the caseating portion.

52:35And then, what happens is it undergoes

52:37fibrosis. What color should we represent

52:39with? Let's do this kind of bluish color

52:40here. So, now it undergoes some

52:43fibrocalcification.

52:45So, now all of this undergoes fibro

52:49calcification

52:51in these areas. That is called a Ranke

52:53complex.

52:54And pretty much this thing is at a point

52:56of where we would consider pretty much

52:57like healed.

52:59So, it's kind of like a healed up Ghon

53:00complex.

53:02There's another thing that's really

53:03interesting.

53:04These Ghon complexes, again, this is

53:06technically dormant. This is technically

53:09a healed dormant spot. There's another

53:11kind of thing that happens, and I

53:13actually found this super interesting

53:14cuz I always wondered, whenever a TB

53:16reactivates, why does it How does it end

53:18up reactivating in the upper lobe of the

53:20lung? I just couldn't figure that out.

53:22It How does it actually get there?

53:24>> [snorts]

53:24>> And so,

53:25it does travel, but it had to be there

53:28even before you undergo the reactivation

53:31process.

53:32And so, what's kind of cool here is

53:35you have here I'm going to say that this

53:36is our Ghon

53:37focus,

53:39outer ring of T cells,

53:42Langhans giant cells. And for right now,

53:45what I'm going to do is I'm going to

53:45have some purple, which is again our

53:48mycobacterium.

53:50This mycobacterium,

53:52a lot of them before they just get ready

53:54to go into this dormancy state, some of

53:56them

53:57kind of hitch a ride

54:00via the bloodstream,

54:02and they hitch a ride via the lymphatic

54:04system.

54:05And they go to other areas of the body

54:07where they can also go and lay dormant.

54:09They can go to the kidneys, they can go

54:10to the brain, they can go to the heart,

54:11they can go all over the dang place. But

54:13this is before, right before they go

54:15into this dormancy state.

54:17One of the areas that it also loves to

54:19go to before it kind of decides to go to

54:20bed

54:22is into the apex of the lungs.

54:24So it uses the bloodstream, it uses the

54:25lymphatic channels to get to the upper

54:27lobes of the lungs.

54:29And then essentially what happens is

54:30they make these like tiny little like

54:32foci. It's almost like a Ghon focus, but

54:36it's so tiny that you can barely see it

54:38on something like a chest X-ray. But you

54:40do get kind of like a little a little

54:42granulomatous formation here. There's

54:44like a little granulomatous formation.

54:46So we started off with a Ghon focus

54:49right here. This is our Ghon

54:53focus.

54:55And then what happened is it spread up

54:57here to the apex of the lungs via the

54:59lymph and the blood. This is called

55:01lymphohematogenous seeding.

55:03This is called a Simon focus. Let's

55:07actually write that down. This is called

55:08a Simon focus.

55:10And that Simon focus is basically some

55:13of the mycobacterium tuberculosis that

55:15traveled from the subpleural middle

55:17lower lobe caseating granuloma to the

55:19apex and it goes into a dormancy state.

55:22And that's all this is, my friends. So,

55:25we have here a Simon focus. So again, a

55:28Ranke complex is basically

55:30fibrocalcification of the Ghon complex.

55:34A Ghon complex that then breaks off and

55:37gives these small little like

55:38microscopic caseating granulomas to the

55:41apex of the lungs before it goes into

55:42dormancy, Simon focus. Ghon focus, just

55:45that subpleural portion of that

55:48caseating granuloma. Hilar

55:49lymphadenopathy is due to swelling that

55:51occurs in the hilar lymph node due to a

55:53caseating granuloma there.

55:55Wow. All right. So, at this point, we

55:58have become infected. The innate

56:00response with your macrophages couldn't

56:02handle it. Who they call in? They call

56:03the TH1 cells. TH1 cells really help to

56:06form the granuloma. You got the

56:08granuloma. Where do they like to form?

56:11In the middle lower lobe of the lung.

56:13Usually near the pleura.

56:15When it undergoes that kind of process,

56:16it can then spread via the lymphatic

56:18system and go to what?

56:21>> [clears throat]

56:21>> It can go to nearby lymph nodes. What's

56:23the lymph nodes? Hilar lymph nodes. When

56:25you get a caseating granuloma in that

56:27portion of the lung plus enlargement of

56:29the hilar lymph node, we call that a

56:31Ghon complex.

56:33This is pretty much is getting ready to

56:34go into dormancy. It's getting ready to

56:35be controlled and go to bed.

56:38If we undergo fibrocalcification,

56:39essentially all this means is it's

56:41undergone a healing process. And this

56:44generally kind of takes some time, but

56:45it's basically healed it's healing.

56:48It's a healing up of that Ghon complex.

56:51Some of them will hitch a ride via the

56:53lymphohematogenous seeding process and

56:54get to the apex of the lung and create a

56:56Simon focus. And this becomes really

56:58critical. This is critical

57:03to reactivation TB because they're

57:06hanging out there already. They are

57:09ready whenever the opportunity arises.

57:11You give them the opportunity, they will

57:13take it and they'll start undergoing

57:16necrosis and liquefactive kind of

57:18processes of that caseous material

57:20in the upper lobe if you let them

57:22reactivate. So, we can't let them, but

57:24that's what will happen. All right.

57:26Let's now take the time to talk about

57:28when a person gets infected,

57:31we undergo the exposure, we go through

57:33all of this immune response. How do I

57:36really, really know if it's latent?

57:39How do I really know if it's primary

57:40progressive? How do I really know if

57:43it's reactivation TB? Not just the

57:45process of it, but how do I truly

57:47understand them based upon the whole

57:49immune response and which one's causing

57:51lung tissue destruction, which one's

57:52going to have an abnormal kind of chest

57:54x-ray, etc. Let's do that. All right, so

57:56we started off here and we said again,

57:57what happened here? We had a person they

58:00get an exposure. They undergo the immune

58:02response, innate, then they go through

58:04the adaptive, which is the TH1, then

58:06from there we create granulomas and

58:08generally these granulomas are

58:09caseating. And again, they often times

58:12will form where?

58:14Initially, they'll form in this kind of

58:16middle lower lobe of the lung, right?

58:19That's where we said and then again, it

58:20can also form here in the hilar lymph

58:22nodes, right?

58:24And

58:25I think the critical thing to remember

58:27here is again, how do we kind of define

58:29this? This was technically in this

58:31scenario, this was called that Ghon

58:33complex, right?

58:35Now,

58:36in most individuals,

58:39we said what what percentage? Probably

58:41greater than 90%, greater than or equal

58:44to 90%, they go into this latent state.

58:48All this means is

58:50is that we were able to contain the TB,

58:53right? So essentially, what that means

58:55is you contained this. You had the

58:57proper immune response.

58:59And whenever this happened,

59:01you were able to pretty much keep these

59:05kind of pathogens snoozing, if you will.

59:08So you kept them in the dormant state,

59:09you basically prevented them from

59:11constantly undergoing replication. So

59:12they're there, but they're not actively

59:14doing any kind of problems and damage.

59:17All right, so you created that you

59:18created these caseating granulomas in

59:19these areas and maybe, maybe they even

59:22underwent fibrocalcification and healed

59:24up.

59:25But in this scenario, you have an

59:27individual who these bacteria are

59:29dormant, but they're not replicating and

59:32causing tissue destruction. That's the

59:34key here. So, latent TB, you got a good

59:36immune response, you go this way. You go

59:39into this dormant state. That's what I

59:40want you to remember. This is basically

59:42is the Mycobacterium tuberculosis are

59:45dormant. They're there. They're not

59:48growing. They're not undergoing any

59:50tissue destruction, but they are there.

59:52The person does have the TB bacteria

59:55there.

59:56All right?

59:57In less than

59:58or equal to

1:00:00Actually, we say less than generally,

1:00:01less than 10%

1:00:04of cases,

1:00:05if you just don't have that proper

1:00:07immune response, right? To be able to

1:00:10contain or to form these granulomas,

1:00:12they may not completely be maintained.

1:00:15So, if you don't have the T cells that

1:00:17are able to keep that interferon gamma

1:00:19coming, you don't have the tumor

1:00:22necrotic factor alpha that's present for

1:00:24macrophages because you're suppressing

1:00:26it in some way, shape, or form. In those

1:00:28scenarios, you can't maintain the

1:00:30granuloma. So, here's what I want you to

1:00:31think about. Here's the granuloma,

1:00:33but we can't any longer keep it formed.

1:00:37And so, because of that,

1:00:39all this Mycobacterium

1:00:41basically starts to grow.

1:00:44And when it grows,

1:00:47it again can grow within this particular

1:00:50portion of where it started its

1:00:51infection, which is usually like the

1:00:52middle,

1:00:53maybe even lower lobes. Again, middle,

1:00:56lower lobes.

1:00:57So, what happened here is you had the

1:00:59caseating granuloma, but you couldn't

1:01:01contain it anymore. You couldn't

1:01:03maintain it. It bust out. The bacteria

1:01:05start causing further destruction.

1:01:08At that point, this is called primary

1:01:11progressive TB. So, again, what's this

1:01:13one called? This is called primary

1:01:19progressive

1:01:21TB.

1:01:23You just basically you couldn't contain

1:01:25it. So in this scenario the

1:01:27Mycobacterium tuberculosis

1:01:30are active

1:01:33and the Mycobacterium tuberculosis is

1:01:35causing

1:01:37damage to the lung tissue.

1:01:40And usually what's interesting about

1:01:42this is that when we think about these

1:01:44like pathogens, they often times in this

1:01:47primary progressive one, they can kind

1:01:49of form like consolidations.

1:01:51Basically kind of just damaged areas of

1:01:53fluid,

1:01:55um exudate, a lot of different types of

1:01:57immune system cells and dead tissue. It

1:01:59kind of accumulates within the alveoli

1:02:00and the bronchioles and it forms kind of

1:02:02like this consolidation, if you will.

1:02:05And so that's one thing that's really

1:02:06kind of unique about primary progressive

1:02:07TB is it's more of

1:02:10a middle lower lobe consolidation.

1:02:15And so sometimes, we'll get into this,

1:02:18is this can kind of mimic like a

1:02:19pneumonia. It's almost like an atypical

1:02:21pneumonia person who just keeps getting

1:02:23treated with antibiotics and they're

1:02:24just not getting better over

1:02:25recurrently. At least three more times

1:02:27they've been treated for this this

1:02:28pneumonia and they're just not getting

1:02:30any better. And you get a chest x-ray

1:02:31and they still have this consolidation

1:02:33that's present in that particular lobe

1:02:34of the lung, middle lower lobes. That is

1:02:37pretty much consistent with that primary

1:02:39progressive TB and especially if they

1:02:41have the

1:02:42what else up here?

1:02:43The hilar

1:02:45lymphadenopathy because again, the

1:02:47bacteria will also not be able to be

1:02:49contained here and it'll grow and

1:02:51potentially cause some enlargement

1:02:52within the lymph nodes.

1:02:54All right. Well, that's one thing.

1:02:57This patient, you went this way because

1:02:59you just didn't have the immune

1:03:01response.

1:03:02This way, you had the immune response.

1:03:05But then at some point, you lost your

1:03:07immune response.

1:03:08Maybe again, person decided to get HIV

1:03:11AIDS. Maybe the person decided to take

1:03:12an immunosuppressant like TNF alpha

1:03:13inhibitor. They took a steroid. They got

1:03:15a transplant. They're on transplant

1:03:16rejection

1:03:17They got acutely ill. Whatever it

1:03:19happened, their immune system activity

1:03:21dropped. Their TNF alpha dropped, their

1:03:22interferon gamma dropped, their T cell

1:03:24level activity dropped, and they no

1:03:26longer could contain these granulomas.

1:03:30But remember, I told you that there's a

1:03:31specific place for reactivation TB.

1:03:34What I want you to remember

1:03:37is that it's usually

1:03:39in these upper lobes.

1:03:41And so what happens is you had these

1:03:44kind of like little focus. What were

1:03:46they called? Come on. I want you guys to

1:03:48remember. Don't you dare say a Ghon

1:03:50focus. It was a

1:03:52Simon focus.

1:03:54And they could have a couple of these in

1:03:55the upper lobes of the lung.

1:03:57They had the Mycobacterium tuberculosis

1:03:59that was there.

1:04:01What happens is you lose the immune

1:04:02activity, all right? You lose the TNF

1:04:05alpha, you lose an interferon gamma. The

1:04:07macrophages go into like this weird

1:04:09destructive state. And they start

1:04:11releasing a bunch of like proteases,

1:04:13metalloproteinases.

1:04:15And all they basically do is they

1:04:17destroy all of that caseous material

1:04:19that was in there. There was some

1:04:20caseating granulomas even in the the

1:04:23dormant state.

1:04:25And what happens is it gets filled with

1:04:27all of this necrotic liquid material.

1:04:30So all we're going to do is we're going

1:04:31to liquefy the caseous necrotic material

1:04:33in these granulomas.

1:04:36Now, we end up with these. Here's what

1:04:39happens.

1:04:41They get close to a bronchi. They get

1:04:44close to a bronchi.

1:04:46And these things are like I mean, I'm

1:04:47not kidding. This necrotic material,

1:04:48imagine like a basically like

1:04:50hydrochloric acid.

1:04:51They get close

1:04:54to the airway and they start eating

1:04:56their way in

1:04:58to the airway.

1:05:00And then this bacteria that's all in

1:05:02this kind of liquefied broth, if you

1:05:04really want to think about it like that,

1:05:06can easily

1:05:08spread

1:05:09via the bronchi all over the dang lungs.

1:05:12And then on top of that, if they decide

1:05:14to cough and they cough up that debris,

1:05:17it basically gets rid of all of that

1:05:19debris that's in these

1:05:22kind of like liquefied cavities, if you

1:05:24will.

1:05:25And so now all of that moved, they

1:05:27coughed all of that up.

1:05:30That allows for them to be extremely

1:05:32potentially contagious.

1:05:34But what it did is

1:05:36is it left these cavities

1:05:39present in the upper lobes of the lungs.

1:05:41And these cavities, which are a mixture

1:05:43of again liquefied necrotic debris and

1:05:46fibrous tissue, these are called

1:05:48fibrocaseous cavities.

1:05:50And so that's really what's key about

1:05:52this one. And this is called

1:05:54reactivation

1:05:56TB.

1:05:57So reactivation TB, the classic thing

1:06:00for this one is cavitary lesions in the

1:06:03upper lobes. That's what I want you to

1:06:05remember differentiating these two from

1:06:07each other. Is again, cavitary

1:06:12lesions. Where?

1:06:15In the apex. Why the apex?

1:06:18Because it's the highest level of oxygen

1:06:19tension. That's where they're going to

1:06:21thrive, that's where they're going to

1:06:22grow, that's where they're going to

1:06:23cause tons and tons of destruction. So,

1:06:25that's one of the big differences

1:06:27between these two. And again, the same

1:06:29concept exists here. These Mycobacterium

1:06:31species, they're all mixed into that

1:06:33liquid like necrotic broth, if you want

1:06:36to think about it. So when we think

1:06:37about the TB here, it's the same thing.

1:06:40They are extremely active.

1:06:42So they have their Mycobacterium

1:06:44tuberculosis is active.

1:06:47And the Mycobacterium tuberculosis is

1:06:49causing What did I write here? Causing

1:06:51damage. Yeah, same same exact thing.

1:06:54It's leading to a point which I'm going

1:06:56to make here in just a second.

1:06:57>> [snorts]

1:06:57>> All right? So they're still causing

1:06:59damage and they are still active in this

1:07:01scenario.

1:07:03Here's the thing. With these two,

1:07:05they'll basically keep kind of spreading

1:07:07throughout the lungs. This will keep

1:07:09spreading throughout the lungs. So,

1:07:11you're going to get from this

1:07:13progressive lung damage. That

1:07:15progressive lung damage that you'll get

1:07:16from both of these, we see as the form

1:07:19of pulmonary TB. Which again, this can

1:07:23look a lot of different ways from both

1:07:24of them.

1:07:25Obviously, in this person they may have

1:07:27some kind of findings of uh pneumonia

1:07:30presentation. Maybe they have a

1:07:31prolonged fever, night sweats, chills.

1:07:34Maybe they have a cough. They have a

1:07:35chest x-ray that shows a consolidate

1:07:36that doesn't go away.

1:07:38Reactivation TB. In this one, they can

1:07:40have

1:07:41pulmonary TB symptoms. Maybe they have a

1:07:43very very productive cough. Maybe they

1:07:45have some weird amorphous breath sounds.

1:07:46They also have fever. They also have

1:07:48night sweats and chills and weight loss.

1:07:50Again, that's the

1:07:52the result of the pulmonary destruction.

1:07:55The other problem here is that these can

1:07:57also spread where? These pathogens can

1:08:00get into the bloodstream. So, that's

1:08:01what we get worried about with these.

1:08:02Is that if these pathogens, they get

1:08:04their way

1:08:06Here they are, let's say.

1:08:09And they get their way in

1:08:11to the lymphatic system

1:08:12or they get out here

1:08:17and they get their way into the

1:08:20circulation.

1:08:22That's kind of a pretty terrible issue.

1:08:24So, if these pathogens decide to spread

1:08:28get into the circulation, they decide to

1:08:30go into the lymphatic circulation, where

1:08:32can they go? Well, from here they can go

1:08:33all over the dang place.

1:08:35When that happens, we call this

1:08:36extra-pulmonary TB.

1:08:39So, this is basically it's using the

1:08:41blood and the lymph as a highway to go

1:08:43and spread to other organs besides the

1:08:44lungs. So, this is called extra-

1:08:48pulmonary

1:08:49TB. So, when a person has active TB,

1:08:53really what we call active TB is where

1:08:55the mycobacterium is active. It's

1:08:57reactivation TB and primary progressive

1:09:00TB. And it can exist in a pulmonary TB

1:09:02form, which is the result of the lung

1:09:04damage, or it can exist in extra

1:09:06pulmonary TB where they go to different

1:09:08organs and cause damage in organs

1:09:10besides the lungs.

1:09:12That's really, really critical here. So,

1:09:14I know that this is a lot of stuff and

1:09:16it's probably something where you're

1:09:17like, do I really need to know all of

1:09:19this stuff? I think everything is really

1:09:21critical when you're trying to build a

1:09:22foundation, but I think a lot of it can

1:09:24come down to a very simple discussion

1:09:26right here. So,

1:09:28when I talk about latent TB,

1:09:30I want you to think about something in

1:09:32both of them. What happened when they

1:09:35both got an infection? When they both

1:09:36got exposed, their macrophages came,

1:09:38they both had a TH1 response.

1:09:40They probably had some degree of

1:09:41interferon gamma that was there,

1:09:43especially in the latent TB. If they got

1:09:45a good immune system, they should have a

1:09:46normal TH1 response. They should be able

1:09:48to push these guys into forming

1:09:50granulomas. So, in other words, if I

1:09:52were to test the T cells one day,

1:09:55and I were to expose them to that TB

1:09:57antigen, would my T cells be able to

1:09:59remember that? That's the key between

1:10:01both of them. And if you're exposed,

1:10:04yes, they should both have that memory,

1:10:07theoretically, right? So, the answer to

1:10:09this is yes. And so, the way that we

1:10:10determine that is we do things like

1:10:11positive um

1:10:13we do what's called um positive um

1:10:15purified protein derivative or a

1:10:17tuberculin skin test essentially, and we

1:10:19inject like 200 different types of

1:10:21mycobacterial antigens into the skin and

1:10:23see if the immune system will at least

1:10:25drive those TH1 cells to help to push

1:10:27and make these granulomas within the

1:10:29skin. All right? And so, this should be

1:10:32positive. They should be positive for

1:10:34this patient if they have that exposure.

1:10:36Same thing over here. In a perfect

1:10:39world, I'm going to be very, very

1:10:40careful because I don't want you guys to

1:10:41always assume this, but in a perfect

1:10:44world, if you did the tuberculin skin

1:10:47test in the purified protein derivative

1:10:48in the active TB, it would also be

1:10:50positive because again, they had the

1:10:52exposure. This is about exposure, all

1:10:55right? It doesn't tell you if they have

1:10:56active TB or not. It just tells you, do

1:10:58they have TH cells that if I expose them

1:11:00to that antigen, they would remember it,

1:11:02meaning I had an exposure.

1:11:04The only thing I will say

1:11:07is that you have to watch out for false

1:11:10negatives.

1:11:12We'll talk about this in the diagnostic

1:11:14section, but in individuals who probably

1:11:16have active TB, what's one of the

1:11:19characteristic components here um

1:11:22in TB, active TB, is they probably have

1:11:25some degree of like an

1:11:26immunosuppression, some degree of it.

1:11:29And so because of that, you can get

1:11:30false negatives if they have an a really

1:11:33deprived immune system. It's called It's

1:11:34called energy.

1:11:36And so we are a little bit more careful

1:11:39of that. But either way, this tells me

1:11:41that they had an exposure.

1:11:44So all this test will tell me is that

1:11:46they had an exposure. What about this?

1:11:49Well, which one did I tell you is their

1:11:51active TB? Well, it's not latent. So if

1:11:54they they're not active, would it cause

1:11:56any types of symptoms and destruction of

1:11:58tissue? No. So there's not going to be

1:12:00There is no destruction.

1:12:03And so all right, here's what I would

1:12:04say. Is there any lung destruction? All

1:12:06right, let's write it like this. No. No

1:12:08lung destruction. All right? Is there

1:12:10lung destruction here? Absolutely there

1:12:12is. How would lung destruction look in

1:12:15these patients? One is they could have

1:12:18the presence of symptoms. If there is no

1:12:21lung destruction, there is no symptoms,

1:12:23theoretically. Theoretically, right? And

1:12:26if there is destruction, theoretically,

1:12:28there is going to be symptoms. So that's

1:12:30one difference here. No lung

1:12:31destruction, theoretically, you should

1:12:33not have any types of pulmonary TB

1:12:35symptoms or extra pulmonary TB symptoms.

1:12:38The same thing here. If you have lung

1:12:39destruction, you theoretically could

1:12:41have some extra pulmonary or pulmonary

1:12:43TB symptoms.

1:12:45Things like fever, cough,

1:12:47night sweats, chills, weight loss. They

1:12:50could have potential pulmonary

1:12:52complications as a result of it. But,

1:12:54that's one thing.

1:12:56The other component here is when I get

1:12:58imaging of the chest,

1:13:00would I see anything that would be

1:13:02abnormal that would suggest lung

1:13:04destruction or any kind of damage

1:13:06theoretically for latent TB? Well, Zach,

1:13:08you did say that I could see healed-up

1:13:11areas. I'm not asking for healed-up

1:13:12areas like a Ranke complex or anything

1:13:14like that. I'm saying, do I see active

1:13:16disease like a consolidation in the

1:13:18middle lower lobe, hilar

1:13:20lymphadenopathy? Do I see any kind of

1:13:22fibrocaseous cavities in the upper lobe?

1:13:25No. And so, generally, these should have

1:13:28no

1:13:29abnormal, and we're going to just use

1:13:31chest x-ray for right now, abnormal

1:13:33chest x-ray. There should not be any

1:13:36abnormal chest x-ray. So, boom.

1:13:39This one, you definitely should have an

1:13:41abnormal chest x-ray.

1:13:43And again, what would it theoretically

1:13:45show?

1:13:46Well, it depends. Are we talking about

1:13:48this as the patient who has something

1:13:50like a primary progressive? They would

1:13:52have that middle lower lobe

1:13:53consolidation, they would have some

1:13:55hilar lymphadenopathy. It would kind of

1:13:57look like pneumonia. This one, they

1:13:59would have some fibrocaseous cavities.

1:14:02Theoretically, they could even have a

1:14:03pneumothorax. This one, you can have

1:14:05pleural effusions. Absolutely, you can

1:14:08have abnormal chest x-rays. But, the big

1:14:10difference here is that they're going to

1:14:11have something abnormal on their imaging

1:14:13that suggests that there is some active

1:14:15destruction. So, this is exposure.

1:14:18This right here is depending upon if

1:14:20they had the immune response capable of

1:14:23containing those granulomas and forming

1:14:26the granulomas. If you had the immune

1:14:28system, you'll probably be okay, and

1:14:29you're going to a dormant state. If you

1:14:31don't have the immune response capable

1:14:33of keeping them dormant, they're going

1:14:34to cause some damage. And that's what

1:14:36makes this really, really critical to

1:14:37understand.

1:14:39All right.

1:14:40Let's move on to the last part here,

1:14:42which is talking about what are these

1:14:44symptoms? What would they potentially

1:14:45look like? All right. well

1:14:47first thing here is pulmonary TB is

1:14:49pretty classic in in the sense that the

1:14:52way I would want you guys to think about

1:14:53it is it's kind of like

1:14:56I I think about finding TB in the

1:14:58vignettes in two forms. One is a new

1:15:00onset uh hemoptysis. That's definitely

1:15:03one way.

1:15:04A second way is probably a person who

1:15:06has

1:15:07a recurrent like progressive pneumonia

1:15:11that's just not getting better with

1:15:12antibiotics. Those are the two ways that

1:15:14I often times will see on the exams that

1:15:16they'll test it. But let's dig into this

1:15:17a little bit more.

1:15:19When you have that immune response

1:15:21that's occurring in these areas

1:15:23I told you that there was macrophages

1:15:25and there were T cells getting involved.

1:15:28And dude, oh dude, are they pumping out

1:15:30tons of things like what? Interleukin 1

1:15:34and TNF alpha.

1:15:36But the big one here is for sure-skis

1:15:39the TNF alpha.

1:15:40These things are getting pumped out. So

1:15:42all of this is happening where they are

1:15:43just pumping out the TNF alpha, the

1:15:45interleukin 1. What do we know about

1:15:47these guys?

1:15:49Well, one is that it causes some

1:15:51involvement of systemic kind of

1:15:54involvement, particularly of the

1:15:55hypothalamus and maybe even our muscles.

1:15:58And so what we see is

1:16:00as we see this kind of activation of

1:16:03these cytokines here. Let's actually

1:16:04we'll bring it down here. We'll say the

1:16:05first thing here that we see

1:16:07is we see an elevation.

1:16:10We see a lot of cytokines from like

1:16:12interleukin 1

1:16:13and TNF alpha. A lot of that systemic

1:16:17kind of involvement here. High levels of

1:16:19this.

1:16:20What happens with these

1:16:22is that whenever they get into the

1:16:23bloodstream, they go to the

1:16:24hypothalamus, activate the hypothalamus.

1:16:26Also, TNF alpha is a really powerful um

1:16:30it really helps with a lot of

1:16:31catabolism, right? Um particularly a lot

1:16:34of cachectic kind of effects of the

1:16:35actual muscle tissue, the lipids. And so

1:16:37we see a lot of cachexia or weight loss

1:16:41as a result. So we see a lot of weight

1:16:43loss

1:16:44that occurs.

1:16:45And that's usually because of the a lot

1:16:47of the catabolism that is occurring

1:16:49within inside of the muscles and the

1:16:50actual fat tissue.

1:16:52The other thing is that we activate the

1:16:53hypothalamus. And the hypothalamus

1:16:55resets our body's thermostat and causes

1:16:57things like fever and

1:17:00night sweats.

1:17:02And so, when an individual who comes in

1:17:05with potentially fever and night sweats

1:17:09and unintentional weight loss, all

1:17:11right? And if I throw in cough, you'd

1:17:13probably be like, "Oh, dude, do they

1:17:15have like lung cancer?" That could be

1:17:17another possibility. You need to get a

1:17:19chest x-ray and say, "Oh, there's a

1:17:20weird kind of like lesion there in the

1:17:21lung."

1:17:23I think the big thing comes down to what

1:17:24was their risk factors for exposure.

1:17:26What was the potential risk factors for

1:17:27potentially progression?

1:17:29But here's another thing.

1:17:31When we talk about this cytokine event,

1:17:33that's one thing that's causing the

1:17:34fever, the night sweats, the weight

1:17:35loss. The second thing is that they most

1:17:37often have a cough. And it's probably

1:17:40going to be more of a productive cough.

1:17:42And I think this productive cough is

1:17:44going to be much, much more likely to be

1:17:47heavily, heavily involved in things like

1:17:49the reactivation TB more than something

1:17:52like the primary progressive TB. It's

1:17:55funny enough, sometimes primary

1:17:56progressive TB can be more asymptomatic

1:17:58than it is symptomatic. That's why we

1:18:00really focus a lot on reactivation TB in

1:18:02your exams. But you definitely can see a

1:18:04productive cough with both of these. You

1:18:06have inflammation. You're You're going

1:18:08to activate J receptors, cough

1:18:09receptors. They're going to cough. And

1:18:11if they have this consolidation, that's

1:18:12going to come with it. If they erode

1:18:15into an airway and some of that liquid

1:18:18necrotic debris gets pushed into the

1:18:19bronchioles, activates inflammatory and

1:18:22activates J receptors, cough receptors,

1:18:23they cough, you're going to get a

1:18:25productive cough, right? Extremely

1:18:27common, but I want you to definitely

1:18:29associate this one

1:18:31probably more so with the reactivation

1:18:36probably more than primary

1:18:40progressive.

1:18:42All right?

1:18:43So, that's the next part that I want you

1:18:45guys to think about is they have a

1:18:46productive cough, fever, night sweats,

1:18:49weight loss.

1:18:50The next thing here is and this is why I

1:18:52tell you, if you have a person with a

1:18:53cough, fever, maybe some weight loss

1:18:56over a long period of time,

1:18:57it kind of acts like maybe especially

1:18:59with a cough and a low-grade fever, you

1:19:01think about pneumonia. And they get

1:19:02antibiotics cuz they have a they have an

1:19:04infiltrate on their chest x-ray that

1:19:05shows that and they just don't get

1:19:07better.

1:19:08Another thing that actually is really

1:19:09important to remember is that sometimes

1:19:10if that kind of reactivation TB, that

1:19:13fibrocaseous cavity erodes and erodes

1:19:15and erodes into the bronchial walls,

1:19:17and it when it does, it erodes into

1:19:19things like the bronchial arteries or

1:19:21the pulmonary artery branches, it can

1:19:23cause

1:19:24them to bleed into the airway. And so

1:19:26because of that, not only can they

1:19:27cough, they can potentially cough up

1:19:30blood. And hemoptysis hemoptysis should

1:19:33always be on your differential in a

1:19:35patient who presents with um TB should

1:19:37always be on the differential in a

1:19:38patient who presents with hemoptysis.

1:19:40So, hemoptysis is another potential

1:19:42symptom manifestation. This one I want

1:19:45to tell you about is extremely rare. I

1:19:47think it's not very common, but I'm

1:19:49going to tell you it and this is usually

1:19:51going to be some type of pneumo- thorax.

1:19:54Usually it's a secondary pneumothorax

1:19:56because there's an underlying lung

1:19:57disease here and it's usually going to

1:19:59have necrosis from those fibrocaseous

1:20:03cavities that erode into the actual lung

1:20:06wall through the visceral pleura and

1:20:08allow for air to escape. So, what I want

1:20:10you to do is look at this kind of

1:20:11diagram. I'm just really just zooming in

1:20:12on this particular area. Here's all this

1:20:14liquefied necrotic debris and it's

1:20:16eroding

1:20:18into the bronchial wall,

1:20:20>> [sighs and gasps]

1:20:20>> eroding here to the alveoli and into the

1:20:23pleura.

1:20:24Here, we have an opportunity for blood

1:20:27to leak out that causes the hemoptysis.

1:20:29And here, we create an opportunity or a

1:20:31channel for air to go from the lungs and

1:20:34go into this kind of plural space. And

1:20:37so now we're going to have air kind of

1:20:39leaking into the plural space. So that's

1:20:41another potential thing to think about.

1:20:43So so far the big ones are fever, night

1:20:46sweats, weight loss, productive cough,

1:20:48hemoptysis. Another thing here

1:20:51is abnormal auscultation.

1:20:53When I go up and put my stethoscope and

1:20:55I listen to the patient,

1:20:56it really could be variable. So what do

1:20:59I mean by that? It's this is not going

1:21:01to be super like helpful to be honest

1:21:03with you because it could sound like

1:21:04they have pneumonia. So they're going to

1:21:06have some abnormal breath sounds.

1:21:09There is one that we potentially

1:21:11associate with TB. It's called amorphous

1:21:17breath sounds.

1:21:19And essentially the way that you could

1:21:21think about it is if you've ever had

1:21:22like a

1:21:23like [snorts] a Coca-Cola bottle that's

1:21:25empty and you try to blow into it, it

1:21:27kind of sounds like a hollow kind of

1:21:28sound. That's really what this is and

1:21:30it's just the sound of air rushing in to

1:21:34the lungs

1:21:36and then moving through that kind of

1:21:37hollow cavity. That's an amorphous

1:21:40breath sound. But other things that you

1:21:42could potentially hear is just you may

1:21:44hear signs of like consolidation. So

1:21:46there could be positive

1:21:48consolidation signs. That means that

1:21:50they could have increased tactile

1:21:52fremitus. They could have dullness to

1:21:53percussion, bronchophony, egophony,

1:21:55whispering pectoriloquy. They could even

1:21:57have bronchial breath sounds, right? But

1:21:59they're going to have positive

1:22:02signs

1:22:03of

1:22:04lobar consolidation.

1:22:08Now, the thing I want you to remember is

1:22:11is with this

1:22:14consoli-

1:22:16-dation.

1:22:17Thing I want you to remember about this

1:22:19is that with the consolidation, which

1:22:21type of TB would I most likely associate

1:22:24this one with? Probably the primary

1:22:26progressive and then the amorphous

1:22:27sounds I would associate more with a

1:22:29cavitary lesion, which is reactivation

1:22:32TB. So, to put it all together, if I had

1:22:34a person who comes in with fever,

1:22:36productive cough, maybe some night

1:22:38sweats, maybe some weight loss, they

1:22:41have amorphous breath sounds,

1:22:43I might start and especially hemoptysis,

1:22:45I'm going to start thinking about the

1:22:46possibility of TB.

1:22:49Now, here's the next component.

1:22:51What if this TB is so vicious

1:22:55that it gains the ability to spread to

1:22:58other places. Maybe it's in this kind of

1:23:00consolidation here

1:23:02and it works its way through the pleura

1:23:06and it gets its way into the pleural

1:23:08space.

1:23:09And now, because of this,

1:23:12I have a fluid

1:23:15that's forming because of all this

1:23:16capillary leakage and inflammation

1:23:18because of the tissue destruction and I

1:23:19got some Mycobacterium tuberculosis in

1:23:21there.

1:23:22What's this called? This is called a TB

1:23:25pleural effusion. That's really what it

1:23:28is. So, that's one thing that can happen

1:23:29is that the TB can spread through the

1:23:32pleura and they can get into the pleural

1:23:34space. You can also get inflammation,

1:23:36it's kind of like a parapneumonic

1:23:37effusion, and then that kind of bacteria

1:23:39jumps right into it. So, this is going

1:23:40to called a TB

1:23:42pleural

1:23:44effusion.

1:23:46So, this is extremely common, I'd say

1:23:48with TB. A lot of the times patients who

1:23:50have TB pretty because it's because that

1:23:52kind of consolidation is subpleural,

1:23:54it's easy for you to get pleural

1:23:55effusions. And so, it's pretty common,

1:23:57especially in TB.

1:23:58So, that's one thing. So, watch out for

1:24:00a TB pleural effusion.

1:24:03The second thing I want you to remember

1:24:04is

1:24:05if these pathogens are eroding their way

1:24:08into the lung tissue and then they get

1:24:11they kind of hop in to your

1:24:14lymphatic circulation or they hop into

1:24:16the um bloodstream, they can kind of

1:24:19spread, right? And this is kind of a

1:24:21really, really dangerous process. When

1:24:23they spread, they can spread to other

1:24:24different areas of the lungs. And when

1:24:26they spread, they cause like these like

1:24:27little inflammatory lesions that look

1:24:29like kind of like little seeds, and they

1:24:31can go everywhere. I'm talking like

1:24:33everywhere throughout the lungs. And

1:24:35that's one thing that we get kind of

1:24:36worried about is when we see like these

1:24:38like small little like looks like millet

1:24:40seeds all over the lungs, this is called

1:24:43miliary TB. This is called miliary

1:24:48TB. So, whenever you see like tons and

1:24:50tons and tons of these like little

1:24:51millet seeds or nodules all over the

1:24:53lungs, you can assume that the pathogen

1:24:56has got into the bloodstream or into the

1:24:57lymphatic system or both, and it's

1:24:59spread throughout all of the lungs, and

1:25:00it's probably also gone into the

1:25:02bloodstream to other areas of the body.

1:25:04Well, what are some of those other

1:25:05areas?

1:25:07Well,

1:25:08one that I get worried about is if it

1:25:10gets into the bloodstream and it gets

1:25:11into the meninges of the brain. All

1:25:12right? That's a pretty terrifying one,

1:25:14and we can get something called TB

1:25:16meningitis. Now, one thing about TB

1:25:19meningitis

1:25:21is that it loves to affect the base of

1:25:23the brain. And so, where you'll probably

1:25:25start to see some problems is right here

1:25:27at the base of the brain. They get a

1:25:29basically kind of a thick exudate that

1:25:31forms around the base of the brain. They

1:25:32get a lot of cranial nerve palsies, like

1:25:33cranial nerve six palsy. They get

1:25:35hydrocephalus, and they'll get

1:25:37meningitis signs. And so, that's really,

1:25:39really important to remember. The other

1:25:41thing

1:25:42is that these pathogens can also get

1:25:44into the bone, the vertebrae.

1:25:46And when they get into the vertebrae,

1:25:47they cause an inflammatory reaction

1:25:48there. And when they cause inflammatory

1:25:50reactions there, it causes basically

1:25:52kind of destruction of the bone. And

1:25:54they get all these kinds of like bone

1:25:55destruction and osteomyelitis kind of

1:25:57effect. Sometimes they can cause the

1:25:59bones to fracture, and if they do kind

1:26:01of fracture, it can cause them to

1:26:03displace into the spinal cord. And so,

1:26:07this is actually called Pott's disease

1:26:09when it's involving the thoracic

1:26:11vertebrae. We get something called uh

1:26:14and just in general, the overall

1:26:15vertebrae. We get something called

1:26:17Pott's

1:26:19disease.

1:26:21All right. So, essentially kind of like

1:26:22osteo- TB osteomyelitis.

1:26:25The next thing is it also can again we

1:26:27told you that if you have these

1:26:29mycobacterium and it's in this kind of

1:26:31area of the lung, it can spread via

1:26:33lymphatic channels to get into your

1:26:35lymph nodes. And then from here it can

1:26:37travel up to your cervical lymph nodes.

1:26:39And really cause a lot of inflammation

1:26:41of the cervical lymph nodes. And

1:26:42sometimes they can get really, really

1:26:44enlarged and inflamed. And we call that

1:26:46TB lymphadenitis.

1:26:49And it's pretty common to affect the

1:26:51cervical lymph nodes. So, TB lymph-

1:26:56adenitis. We actually give this a very

1:26:59special name

1:27:01and we call this a scrofula.

1:27:04All right. It's called a scrofula.

1:27:07So, it's essentially more likely that

1:27:09the involvement of the cervical lymph

1:27:10node that we're seeing some kind of

1:27:12inflammation

1:27:14involvement. All right. So, we got the

1:27:17meninges at the base of the brain. We

1:27:18got the actual vertebrae which can cause

1:27:21these kinds of lesions to occur within

1:27:23the bone, inflammation. So, you get

1:27:25basically an osteomyelitis. It can cause

1:27:27fractures. They can displace. They can

1:27:28cause compression of the spinal cord.

1:27:30Here you get enlargement of the cervical

1:27:32lymph nodes.

1:27:33And then another thing is

1:27:35it can actually involve the pericardium.

1:27:38And when it involves the pericardium,

1:27:39it's going to cause inflammation of the

1:27:41pericardium at first. So, it can kind of

1:27:42cause like an acute pericarditis. And

1:27:44so, they usually get kind of an effusion

1:27:46that can occur here. So, pericarditis is

1:27:48almost always to a degree associated

1:27:50with like a degree of a

1:27:51effusion. All right. The problem with

1:27:53this is that TB continues to cause

1:27:56destruction. And eventually repeated

1:27:58bouts of pericarditis can lead to

1:28:00something called constrictive

1:28:02pericarditis. So, when I say that a

1:28:04patient can get pericarditis,

1:28:07I what I really get worried about

1:28:10Oops.

1:28:11is I get really worried about

1:28:13constrictive pericarditis. So, let's

1:28:15actually write this down. Let's call it

1:28:16TB

1:28:18pericarditis. And one of the biggest

1:28:20concerns with this is that yes, it may

1:28:22cause pericardial inflammation. So, they

1:28:23get pleuritic chest pain. They also can

1:28:25have that radiate to the trapezius. On

1:28:28top of that, they get up EKG changes.

1:28:29They get up a pericardial effusion. They

1:28:30could have kind of a scratchy type of

1:28:33heart sounds, which potentially could be

1:28:35present or decreased heart sounds.

1:28:37Either way, they're going to have that.

1:28:39But one of the biggest risks is that if

1:28:40it keeps keeps occurring, it undergoes

1:28:42fibrosis

1:28:43of the pericardium. And then eventually

1:28:45that can cause constrictive

1:28:47pericarditis, which can cause right

1:28:48heart failure. So, that's one thing to

1:28:50remember.

1:28:52The next thing is the TB can also spread

1:28:54and get into the peritoneum. It can get

1:28:57into the peritoneal fluid. And you can

1:28:59get a lot of inflammation of the

1:29:00peritoneum, and you can get some ascites

1:29:02that forms. So, that's another thing. Is

1:29:04not only are you getting

1:29:06um ascites, but you're also getting

1:29:08potentially some thickening

1:29:10of the peritoneum.

1:29:12And what is this here called? This is

1:29:13called TB peritonitis.

1:29:16Again, it's called TB

1:29:19peritonitis. And one of the key things

1:29:20here is this may cause things like

1:29:22abdominal pain, but you're probably

1:29:23going to see a patient who presents with

1:29:24underlying ascites. So, here they'll

1:29:26present with maybe some dullness to

1:29:28percussion, decreased breath sounds in

1:29:30the affected side, pleuritic chest pain.

1:29:31Here, they may have headache. They may

1:29:33have fever. They may have some cranial

1:29:34nerve six palsy. They may have some

1:29:36meningeal signs. Here, they're going to

1:29:38have potentially pain over the

1:29:39vertebrae. So, they're going to have

1:29:40pain over maybe the thoracic spine.

1:29:43It'll be tender to palpation. They may

1:29:45even have some neurological deficits.

1:29:47Here, they're going to have some really

1:29:48significantly enlarged cervical lymph

1:29:50nodes.

1:29:51Here, they can have chest pain. They can

1:29:53have potentially some abnormal heart

1:29:55sounds where it's either diminished or

1:29:57it sounds kind of like a

1:29:59It's like kind of scratching. So, like a

1:30:01friction rub essentially.

1:30:03And if it doesn't get better, it can

1:30:04cause constrictive pericarditis, which

1:30:06can cause heart failure, particularly of

1:30:07the right side. It can spread to the

1:30:09peritoneum and cause acidic fluid

1:30:10accumulation and thickening of the

1:30:11peritoneum. This can cause abdominal

1:30:13pain and overall ascites.

1:30:15On top of that,

1:30:17it can also spread to the adrenal

1:30:19glands,

1:30:21especially the adrenal cortex, and it's

1:30:22usually both the adrenal cortexes, and

1:30:24it causes destruction of the adrenal

1:30:27cortex. When you get destruction of that

1:30:28adrenal cortex, you lose the ability to