How Hantavirus Kills

0:00 med.com.

0:02 Welcome to another MedCram video.

0:03 Today we're going to talk about how hiviruses actually kill.

0:07 And I want to be specific here.

0:09 There's two types of havirus.

0:11 There's those in North and South America, which is what is in the news lately.

0:15 And there's also the oldw world hiviruses which are in Europe and Asia.

0:21 We're not going to be talking about those.

0:22 Those particularly hit the kidneys and the mortality

0:25 rates are lower like 1 to 15%.

0:28 Today we're going to talk about North

0:30 and South America and specifically the Andes type

0:32 of pantivirus which has a much higher lethality

0:36 or mortality rate about 40% and we're going to talk about the syndrome that is

0:41 associated with that which is cardiopulmonary and why

0:43 this seems to do so poorly and why

0:47 people need intensive care services when they get this.

0:50 So let's get started and what I'm drawing here is a lung alvolus.

0:55 So this is where gas exchange occurs and what we

0:58 have here is the pulmonary artery and there are de

1:02 oxygenated red blood cells that are coming towards the interface

1:07 between the pulmonary vascule and the alvoli or the air pockets.

1:12 Then we get oxygen which is here and it's

1:15 going to diffuse into that capillary where it's

1:18 very thin and it's going to cause oxygenation

1:21 of the red blood cells into the pulmonary vein.

1:24 So this is the key to understand is

1:26 that there are large numbers of these units where oxygen

1:31 is coming in and carbon dioxide is being let

1:35 off and this is where gas exchange is occurring.

1:37 So oxygen is going in, carbon dioxide is coming out.

1:41 And the key here to understand is that there are cells,

1:45 these are the cells right here that line this vascule.

1:50 And these are known as endothelial cells.

1:52 And they are very thin.

1:54 And they need to be very thin because you need

1:55 to have these gases be able to go through these compartments,

2:00 the alvolar compartment and the intravascular compartment,

2:03 and allow for exchange.

2:05 If these things become damaged or it becomes thicker,

2:08 you're not going to be able to get the same type of gas exchange.

2:11 So, what we see happening here is the virus,

2:15 which I'll have here in green, comes in to the alvolar space.

2:19 Now, this can happen because the viruses are in the mouse

2:23 droppings or they're in the mouse urine or in the mouse saliva.

2:27 And if they get stirred up because someone is sweeping or because

2:30 someone is vacuuming and they're not

2:32 wearing the appropriate mask and protection,

2:35 they could inhale these viral particles.

2:37 And then these viral particles will infect and they'll go

2:40 through and they specifically like to infect these endothelial cells.

2:46 And because they're being inhaled,

2:48 this is the vascule that they infect, the pulmonary vasculature.

2:52 And to make a long story short, which we'll go into, essentially what happens is

2:56 is that when they infect these endothelial cells,

2:59 this infection can go on for days if it's

3:02 not taken care of by the innate immune system, which includes interferon.

3:06 We've talked about this before, but what these viral particles do is

3:10 it suppresses the body's ability to make interferon.

3:13 That's why this thing goes on for such a long time.

3:16 These symptoms can go on for days before the ultimate collapse occurs.

3:21 And what causes the ultimate collapse and ends up killing the patient

3:24 is that these endothelial cells which

3:27 should have very tight junctions between them.

3:29 These junctions have to be very tight because all of this plasma,

3:33 all of this black stuff in here inside the intravascular space is fluid.

3:37 If these junctions weren't tight,

3:39 then what would happen is that the plasma would leak from the vascular

3:44 space into the space where the air is supposed to be.

3:48 And that's exactly what happens in this situation

3:51 is that these tight junctions become very leaky.

3:54 And this area here fills up with fluids.

3:58 And sometimes the junctions can become so leaky

4:00 that in fact red blood cells get in here.

4:03 And the patient's lungs essentially fill up with blood.

4:07 Now you can see that there's two problems you're seeing here.

4:09 The first problem is in this space here

4:12 that it should be dry and it's becoming wet.

4:15 And that's a problem because you cannot have good gas exchange.

4:19 The other thing that you'll see here is that all of the fluid that's

4:22 in here in the vascule you're pumping around your body should be very wet.

4:26 A lot of fluid and it's becoming very dry.

4:29 And so what happens is you become in hypoalmic shock or you

4:33 have less volume in your vascule and your organs don't get enough perusion.

4:39 So you start to go into failure because not enough blood

4:41 is circulating around and your lungs start to fill up with fluid.

4:44 you don't get enough oxygen.

4:45 And you can see that that's a real problem.

4:47 And the epicenter of all of this are

4:49 the tight junctions that we see in these endothelial cells.

4:53 You should have a nice tight junction.

4:55 We'll use red here again since we used red before.

4:58 So here's the red endothelial cells and they're very tight

5:02 junctions so that when you have fluid on this side,

5:05 it can't get into this airspace.

5:07 But when the viral infection comes, what that turns into is something like this.

5:12 It becomes leaky.

5:13 And so what happens is fluid is able

5:15 to leak from one place to another and that's

5:19 making this area dry and this area wet

5:22 and that's exactly the wrong thing to have.

5:24 Of course what happens is that this inflammation

5:27 can also cause problems with the heart.

5:29 You can get arrhythmias and it's likely the reason

5:31 why people just all of a sudden collapse.

5:33 They have low oxygen.

5:35 They are in shock.

5:36 They can't breathe.

5:37 They're trying to breathe which requires more pumping

5:39 from the heart until finally the body just cannot give anymore.

5:43 So let's go through this again in stages.

5:45 Exposure is the first phase and that's going to happen when you have fevers,

5:49 fatigue, myalgas, headaches, chills, dizziness,

5:52 abdominal pain, nausea, vomiting, diarrhea.

5:54 It doesn't look like a pulmonary disaster.

5:56 It just looks like a regular flu type of virus.

6:00 And that goes on for 4 to 10 days.

6:02 This is the magic window where you can actually do something about it.

6:06 If you can improve the innate immune system, if you can improve interferon,

6:10 we talked about hot and cold as a potential intervention.

6:13 We've talked about the role of interferon.

6:15 It's this first area here where you have exposure and then it goes,

6:19 as we mentioned, to the early phase.

6:22 That's where you have this flu-l like feeling.

6:25 Then you go to stage three where you have the endothelial phase.

6:30 That's when it infects the endothelium as we talked about here.

6:33 Phase four is where you get leaky

6:35 pipe and the infected endothelium becomes abnormally permeable.

6:39 And there's several overlapping mechanisms that have

6:42 been proposed there as to how that works.

6:44 For you want to get technical, there's something called veg F,

6:48 veg F sensitization where you have

6:50 pathogenic haviruses can make endothelial cells more

6:53 responsive to veg F which is a messenger and a permeability promoting factor.

6:58 They talk about increased VEGF signaling and degradation or disruption

7:02 of the endothelial junction controls including

7:05 some related mechanisms associated with that.

7:07 There's also something called beta 3 integrine.

7:11 They'll talk about that in the literature.

7:13 Canviruses use endothelial receptors including beta 3 integrine

7:18 and protocadherin 1 signaling for attachment and entry.

7:23 And the infection can disregulate non-litic endothelial barrier function.

7:27 That's another one there.

7:28 We'll talk about the proteins on the surface

7:30 of the endothelial cells here in just a second.

7:32 There's other immune amplifications that are here called

7:36 CD8s and these are a type of tea cells.

7:39 The CD8 T- cell responses and inflammatory mediators may contribute as well.

7:43 Has specific T- cell responses in the pulmonary cardio version of HTirus have

7:49 actually correlated with disease severity suggesting

7:52 that imunopathology is part of the injury.

7:55 Then there's also another one called

7:56 Brady Kynan Pathways that's been implemented.

7:59 And I'm bringing up all these things here now

8:01 because I'm going to test you at the end.

8:03 But these are areas of research that people are looking into to see if they can

8:06 modulate this so that you don't get this problem

8:10 where the things that are dry become wet.

8:12 The things that are wet become dry because that is the problem.

8:16 So the bottom line here is that hivirus

8:19 turns a normally tight capillary bed into a seieve.

8:22 Not necessarily by ripping the vessel apart,

8:24 but by changing the signaling that keeps the barrier sealed.

8:28 This is sometimes supposed to be leaky.

8:30 So you can have inflammation fix things.

8:32 But what hivirus does is it abnormally makes

8:35 it leaky and then you have a real problem.

8:37 What happens clinically is you'll see this on a chest X-ray.

8:41 Looks like this.

8:42 This is the heart.

8:42 Is you'll start to get bilateral pulmonary infiltrates in the middle.

8:46 We call that noncardiogenic pulmonary edema.

8:49 And this is very similar to what we saw with CO

8:52 19 because you have fluid where fluid should not be.

8:54 That non-cardiogenic pulmonary edema simply means that fluid is being backed

8:58 up into the alvololis here and it's filling up with fluid.

9:02 And it's not because of the fact

9:04 that the heart which sits over here isn't pumping

9:08 forward and things are backing up and causing

9:10 pressure to push this stuff into the alvolus.

9:12 It's not because of that.

9:13 It's simply because these capillaries here are so leaky that the fluid

9:17 is just leaking out and filling up these alvoli so you can't breathe.

9:21 So as we talked about when this fluid is all

9:23 leaking out the amount of fluid that's left in the vascule

9:27 starts to drop and as a result the heart

9:30 it doesn't get enough profusion the heart starts to fail.

9:32 you get increased pulmonary vascular permeability,

9:35 extravascular lung water, hypoalmia,

9:38 reduced stroke volume, myioardial dysfunction,

9:40 and then finally circulatory impairment.

9:43 The bottom line here is that the lungs are wet

9:45 and the circulation is dry and that's what leads to death.

9:48 So obviously if you're in the intensive care unit,

9:50 you can actually hydrate people, monitor them.

9:52 You have to be careful of course cuz if

9:54 you give too much fluid here in the intravascular space,

9:57 it could flood this space even more.

9:58 This is why intubation is so key in these types of patients

10:02 because when you intubate somebody and put them on a ventilator,

10:05 you're actually pushing air down into the alvolus

10:09 and you're pushing this fluid back out into the vascule.

10:13 And that's important because then you can start to dry out

10:16 these alvoli and push the fluid back into the intravascular space.

10:21 And you can support these people long enough

10:24 so that they can actually improve and get better.

10:26 And they are even able to do ECMO.

10:29 ECMO is a way of basically bypassing the lungs

10:32 and oxygenating the blood so that the patient's

10:35 lungs can get better on their own and the patient doesn't die in the process.

10:39 So ECMO has actually dramatically improved survival in patients with hivirus.

10:44 The problem is that there's just not enough ECMO

10:47 centers to treat everybody that you have in an outbreak.

10:52 So if you look at the data, the CDC says that HPS or HNTA pulmonary syndrome

10:56 is fatal in about four out of 10 infected patients.

10:59 Of course, that number goes down if you have ECMO, if you have support ICU.

11:02 The technical number that they use is 38%

11:06 mortality among people who develop the respiratory symptoms.

11:09 So that's why early ICU admission is so key after you have exposure,

11:14 the early phase where you feel like you've got the flu.

11:16 Number three, after you have endothelial damage.

11:19 Number four, after the leaky pipe,

11:22 now you're getting into like the pulmonary edema,

11:25 which is number five right there.

11:27 And then number six is where you have depletion of the intravascular space.

11:31 And then finally, number seven is where

11:33 your heart fails and you basically collapse.

11:36 Now, I wanted to just give you a little

11:37 bit of education in terms of the proteins.

11:40 Here is our virus.

11:42 This is our havirus and it is going to bond to this endothelial cell right here.

11:49 We've talked about the spike protein of SARS KV2 and we've

11:54 talked about the A2 receptor on the surface of the cell.

11:57 There's something similar going on here and I'll tell

11:59 you what those names are here for this hivirus.

12:02 And since we're talking about a specific type of havirus called the Andes,

12:06 I will be specific to the Andes virus.

12:09 It's the Andes Hantha virus.

12:12 And specifically what we're looking at here is a protein

12:15 on the surface of that virus called the GN or the GC protein.

12:22 So GNGC is the protein on the surface of the Andes hivirus.

12:28 And what does it bind to?

12:29 There's two types of proteins or receptors

12:32 on the surface of this endothelial cell.

12:35 One of them is called protocadherin 1.

12:38 The abbreviation for that since it's such a long word is P CDH1 and that's what

12:44 we see in the Andes virus and the one in North America called the synobi virus.

12:51 But if you're looking at the older

12:52 pathogenic literature on this, the one that they

12:55 have identified on there as well is the B3 integrants or the beta 3 integrants.

13:02 And notice we talked about that down here

13:05 as with the leakiness and that's what may be going on.

13:08 So for this type of antivirus, the Andes,

13:10 think of G&GC which is on the virus side and think

13:14 of the protocadherin one protein on the surface of the endothelian cell.

13:19 So what does this all mean?

13:20 This is the sort of slow motion rolling

13:24 disaster that happens in people who get infected.

13:26 What the virus does in the early phase

13:28 here is it tries to suppress interferon so

13:31 it can burn along as long as it can and infect as many cells as it can.

13:36 the more endothelial cells that it infects,

13:39 by the time it gets to the endothelial phase and the leaky pipe phase,

13:43 there's much more leaking going on.

13:45 The people that survive hivirus are those that mount a interferon response,

13:50 which is so robust that it's able to limit

13:53 the number of endothelial cells that get infected.

13:56 So that when the leaky pipe phase occurs,

13:59 there's much less fluid and there's much less shock.

14:02 So what's the key here?

14:03 The key here is getting early treatment and the key

14:07 is limiting the amount of endothelial cells that gets infected.

14:13 And I've said this before and I'll say this again.

14:15 I think the key here is knocking out the virus's

14:19 ability to suppress your own body's ability to make its interferon.

14:24 And we've talked about one of the things that can

14:26 do that, which is making sure that there is elevated temperature.

14:30 But that needs to be done in a judicious way.

14:32 We'll also talk about in future videos some

14:34 of the trials going on looking at antivirals,

14:36 but again that needs to be done early.

14:39 There's no distinction here in the early

14:40 phase that tells you you have antivirus.

14:43 You just feel bad.

14:44 You have all of the symptoms of a viral infection.

14:47 It's not until you get to the leaky pipe phase after

14:50 your endothelial cells have been infected that it's getting too late

14:53 and you need to make sure that you show up

14:55 to an intensive care unit so that they can manage the alvoli,

14:59 making sure that they don't get flooded

15:00 and making sure you're getting enough aggressive

15:02 IV fluid hydration so that you don't

15:05 go into cardiovascular collapse and have cardiac arrest.

15:09 So this is how antivirus kills.

15:11 Knowledge is power.

15:12 If we know how to break this chain,

15:14 we can improve survival in patients who have hivirus.

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