PATHOGENESIS OF ROSALIA HF

"It is an RNA virus that belongs to the fifth class of the Baltimore classifications, the Mononegavirales order, and the Filoviridae family. But there are no records of its nucleic acid and manifested form, and it is assumed to be a new variety of virus."

「ボルティモア分類５群、モノネガ目、フィロ科に属するRNAウィルスです。但し、核酸及び発現形式に記録は無く、新種のウィルスと予測されます。」

"After all... it's a new kind... so. We named it the Rosalia virus."

「やはり…新種なのですね…そうだ。俺たちはコイツをロザリアウィルスと名付けた。」



WHAT THE HELL ARE RONI AND GABE TALKING ABOUT?

Class V is comprised of negative-sense single-strand RNA viruses. The Mononegavirales order comprises of viruses that have a non-segmented, negative-sense RNA genome. The Filoviridae family is specific family of viruses that comprises of viruses with fibrous strand-like virions (virus particles). So the Rosalia virus is a negative-sense single-strand RNA virus with a non-segmented, negative-sense RNA genome and virions with an appearance of fibrous strands.

The Filoviridae family also contains two genera of viruses; Marburgvirus, which has one known species, and the famous Ebolavirus, which has several species. If you've heard about Ebola, it's most likely you've heard about Zaire ebolavirus, which has a case fatality rate up to 90%. The other Ebolavirus species are slightly less deadly, with Sudan ebolavirus averaging at about 50% and Reston ebolavirus being asymptomatic in humans (but with a high mortality in monkeys). Looking at the image ATLUS provided us of the Rosalia virus, I would say that it is structurally closer to the Marburg virus, but looking at everything else, it's pathologically closer to Ebola Zaire. Both the Marburg and Ebola viruses are known for causing viral hemorrhagic fever, but the similarity of the course of infection is closer to Ebola Zaire's.

Just for fun, if I were to classify the Rosalia virus using common virus nomenclature, the specific classification would be:

Class: V. Order: Mononegavirales. Family: Filoviridae. Genera: Rosaliavirus. Species: Portland rosaliavirus (PROSV).

Also for fun, the Rosalia virus would most likely be considered a Biosafety Level 4 agent. (There are four levels under this classification: Level 1, which rarely cause any illness in humans; Level 2, which cause moderate illness in humans, or cause severe illness that isn't easily transmissible [ex: Influenza, HIV]; Level 3, which cause severe or fatal illness in humans and are highly infectious, but can be treated easily and or vaccinated against [ex: Rabies]; and Level 4, which cause severe or fatal illness in humans, are highly infectious, and have no vaccine or treatment [ex: most viral hemorrhagic fevers].)

Although by the end of Trauma Team, the Rosalia virus would probably be dropped down to Level 3 due to the highly successful antibody serum the team created.

With viral hemorrhagic fevers, naming of the disease the virus causes usually consists of tacking the name of the virus or the location of the outbreak in front of "hemorrhagic fever." Since it's highly unlikely any location in the United States would let that fly, the name of the disease caused by Rosaliavirus would probably be "Rosalia Hemorrhagic Fever."

And again, for fun, if a doctor were to write down your diagnosis of Rosalia Hemorrhagic Fever using the International Statistical Classification of Diseases (ICD), he would write 065.8 if using ICD-9 and A98.8 if using ICD-10.

Speaking of which, how would a doctor diagnose you with Rosalia Hemorrhagic Fever in the first place? Common guidelines for suspecting a case of viral hemorrhagic fever in a patient include the following criteria: fever of 101°F or higher with less than three weeks duration, no predisposition for hemorrhagic manifestations, no established alternative diagnosis, and two of the following; hemorrhagic or purple rash, epistaxis (nose bleed), hematemesis (vomiting blood), hemoptysis (coughing up blood), melena or hematochezia (black and tarry or bright red feces), or other signs of bleeding.



HOW EXACTLY WOULD THE ROSALIA VIRUS AFFECT YOU AS ROSALIA HEMORRHAGIC FEVER?

I'm not very good at professional essays (that's why I always did poorly on those things in school), so I'm just going to describe what exactly might happen to you once you contracted Portland rosaliavirus (LOL). This is what I believe to the most probable course of infection based on symptoms exhibited by patients in the game and known viral hemorrhagic fevers. Let's begin (the operation)!

It all starts, of course, with you contracting the virus. You most likely managed this through contact with scales shed from monarch butterfly vectors; it doesn't appear to be transmitted through close contact with an infected person, unlike its sibling viruses. There are too many accounts of direct contact with an infected person, sometimes even their blood, without consequence to support such a route of transmission. The virus may, however, be transmitted through contaminated material coming into contact with susceptible mucous membranes (eyes, nose, mouth, and sexual organs). That's probably how butterfly scales became a source of infection in the first place: scales swirling around in the wind got into your eyes or your mouth, or landed on the food you were eating. It wouldn't take very many of these scales to do damage, either. While most viruses have a fairly high infectious dose (amount of individual virus particles needed for someone to get sick), viruses in the filoviridae family tend not to need nearly as much. For example, HIV requires something over several hundred particles: if you accidentally prick yourself with a needle contaminated with HIV, you have only a one-percent chance of contracting it. Filoviruses, on the other hand, require as little as ten particles, and that's the high end of the spectrum-- sometimes one virus is enough to successfully develop the infection. If you pricked yourself with one of those needles, you got it. Once that scale (or otherwise infected material) got into your mucosa, you didn't really stand much of a chance. The virus is now in your body.

At the point of entry, nearby white blood cells-- macrophages, the front lines of your initial immune system response-- notice the intruder and move to destroy it, just like it would with any other virus or bacteria that may try to invade your body. Unfortunately for the macrophage, it just so happens to be one of this virus's favorite targets. Instead of destroying the intruder, the virus attaches itself to the cell and fuses to its membrane, injecting its genome inside the cell. The virus genome takes command of the cell's nucleus, using the cell's own mechanisms and turning them on itself in order to produce more virus. One possible reason why filoviruses in particular are so deadly may be because their long, fibrous strands allow them to clump together inside the host cell, provding more room for the cell to create more and more viruses before it bursts. Most viruses tend to be bulky, or don't have much give, making it harder for them to clump together. It's also possible that the thin strands allow the virions to escape the host cell without causing too much damage to the cell, giving it even more room to make even more virus. Because the virus has commandeered the white blood cell, it stops functioning like one, and it is left unable to signal to the rest of your body that an invasion is taking place. However, it is able to signal other monocytes and macrophages toward it, purely in the virus's own interest, in order to provide more of its favorite targets. The virus has taken your body's method of fighting it off and turned them against you. And it doesn't stop there, either: the virus also uses the infected white blood cells to travel to other parts of your body. White blood cells have the ability to travel pretty much anywhere in your body, and now, the virus has that ability too.

Once the virus's preferred mode of transportation arrive at these new locations, fresh viruses escape from the infected white blood cells and attack the cells that make up your organ tissues. Each virus has a number of proteins on its surface that help aid it in its conquest of your body; how many depends on the virus itself, but that isn't what's important. What's important is, inside these tissue cells, one of these proteins interferes with the newly infected cell's copy of the genes that inhibit unwanted cell growth. This causes them to start replicating out of control, and form tumors. As the tumors grow in size, the virus also replicates inside the out-of-control cells. It's using the tumors as fodder to help step up the production of more viruses. Depending on where exactly in your body the bloodstream had dropped the viruses off, the growing, virus-filled tumors start causing symptoms not unlike malignant cancers of those organ tissues. Once the tumors reach a certain size, the interfering proteins induce apoptosis-- the pre-planned death of the infected cells, programmed into the cell by the virus to occur at that size-- and the tumors "burst," decaying and releasing all the virus particles inside to seek out new targets. This helps spread the virus throughout your body. The body hasn't recognized the virus as an infection yet, but it won't be long until, thanks to these virus tumors, the virus load in your body eventually rises high enough that not even the virus's suppression of your body's immune response can hide its existence.

Finally detecting the intruder, your body starts taking steps to get rid of it. It's at this point where there's enough virus inside you to pass it on to others. You pass out of the incubation period and into the prodromal phrase: the initial symptoms that indicate the beginning of an infection. You start complaining of flu-like symptoms-- fever, headache, malaise (general feeling of sickness); the symptoms those with viral hemorrhagic fevers typically present with. You feel weak, and you don't want to move much; your body's preserving its strength for the battle. You feel hot; your body's raising your core temperature in the hopes that the heat will help kill off the virus. You probably think, at this point, you are coming down with the flu, and plan accordingly-- rest for the next few days and drink lots of water in the meantime. Without any indication that there's been a problem, your body starts starts sending out signals to your immune system: send out the specialized lymphocytes to combat this new threat. Unfortunately, the damage to your immune system has already been done. The infected white blood cells, the monocytes and macrophages, release soluble factors as they malfunction due to the virus inside them. Because of the soluble factors, those specialized killer cells are damaged and don't function like they should, and your body considers them to be defective and kills them off on its own accord. Despite all this, even though their numbers are starting to diminish, the virus still likes to use those white blood cells for travel because of their accessibility; and once it reaches your liver, the real problems begin.

There, the virus induces overexposure of something known as "tissue factor," which helps with coagulation (clotting of your blood). This sets off a response known as disseminated intravascular coagulopathy, which is a major feature of filovirus-induced hemorrhagic fevers. Normally, tissue factor is released when your body sustains injuries and trauma to blood vessels and tissue, like when you accidentally slice your finger open or you scrape your leg, and the white blood cells that respond to the site produce cytokines that trigger the release. This leads to the formation of clots in your blood, a spongy mass that plugs the wound to prevent any more blood loss. The only problem is, you don't have any injuries to plug, so this formation of clots is completely unnecessary. And not only that, while the release of tissue factor normally ceases after bleeding stops, the virus continues to exploit it, and consumes the platelets and fibrinogen that are used in clot formation. As a result, tiny clots travel through your bloodstream without a purpose, sometimes combining with other clots to form bigger clots. And sometimes, they get lodged in your blood vessels, restricting blood flow, or worse-- blocking ones that supply your organs with the blood and nutrients they need. Since your organs can't function without those vessels, they begin shutting down, and the tissues start turning black and developing necrosis. Depending on the organ or organs that were blocked, the virus has caused more problems with your body. At the same time, the blood itself is depleted of its clotting factors, and would be unable to stop the bleeding if you were to receive any injuries.

Another major feature is high fevers. Your body's still trying to fight off the infection, with what little defense it has left; unfortunately, without much of an immune system left, there's really only one other way to do that. Ever since you first developed the fever, your body had been raising it higher and higher in the hopes that, even though it hasn't been successful in killing off the virus yet, a higher temperature might do the trick. The problem is, it doesn't know when to stop, and your body wasn't made for that kind of heat. Once your core temperature reaches 104°F and higher, your brain starts to malfunction. The neurons in your brain overheat, which sometimes results in temporary damage to the receptors, and the discharged signals cause your body to go into convulsions. Convulsions could also be caused as a result of neurological dysfunction; as this tends to be a systemic illness, there is often multi-organ involvement. Hepatic, pulmonary, and renal involvment are the most common, although the central nervous system is sometimes affected as well.

Meanwhile, your blood, without the ability to clot, continues to flow. And the virus has in its sights yet another one of its favorite targets: the endothelial cells that make up the walls of your blood vessels. If you thought the clots blocking the vessels were bad enough, now the virus is destroying the blood vessels themselves. Your blood leaks through the damaged walls, and pool underneath your skin, causing the distinct bruises viral hemorrhagic fevers are known for. The capillaries in your eyeballs rupture, giving your eyes that bloodshot look. More blood seeps out of your nose and into your stomach; the blood irritates your stomach lining, and your gastrointestinal walls force it up and out through your mouth. The other end does the same. Puncture sites, including those caused by medical procedures such as injections and intravenous catheters, ooze blood without any signs of stopping. Your gums bleed, and so do other mucous membranes. Anywhere where there's blood vessels and capillaries, blood will escape through the damaged walls. All this blood loss eventually leads to hypovolemic shock-- your body's cells and tissues stop functioning properly due to lack of plasma (the fluid that carries your blood cells and the nutrients). Your heart and respiratory rates increase, trying to pump your blood faster to make up for the blood loss-- because your body doesn't have as much plasma as it should, it has to work overtime. Your blood pressure drops; as the volume drops, there's less pressure. The decrease of oxygen supplied to your brain leads to your brain starting to shut down, since it can't function without it. As it shuts down, you become confused; your consciousness starts slipping. If it continues, you eventually end up in a coma.

Hopefully, before it reaches that point, you realize there's something very wrong with you and bring yourself to a doctor. When presented with the classic symptoms of a viral hemorrhagic fever, they will most likely isolate you and send for an Enzyme-Linked Immunosorbent Assay (ELISA) test (most likely the test used in the game) to confirm their suspicions. There's no screwing around with something like this. VHF Isolation procedures are put into effect. They hook you up to a ventilator to give you rich oxygen to make up for your body's inability to draw what it needs from the air. If it's severe enough, they might even slide a tube down your trachea and into your lungs, and do all the work for you. They run an intravenous line into your arm to replenish nutrients your body needs and maintain fluid and electrolyte balance, and if the bleeding's bad enough, they set up blood transfusions too. Sometimes they will administer treatments that help your blood to clot again, like concentrates of clotting factors, platelets, and fresh frozen plasma, but most importantly, they give you a bag full of antibodies through the IV. Since many of those that die from viral hemorrhagic fever hadn't had time to build up enough antibodies on their own, the more antibodies you receive, the better.

But, if you wait too long, most viral hemorrhagic fever deaths are contributed to hypovolemic shock or multiple organ failure. Either you've lost too much blood (mostly internal through damaged blood vessels) to keep your body functioning, or more likely, the combination of blood loss and clots blocking important vessels cause your organs to die. Eventually, due to the extensive damage, everything else will follow suit and shut down as well.

(Contrary to popular belief by people who have read a little on viral hemorrhagic fevers, they do not turn your organs into soup. That's just sensationalism. I'm blaming a certain book about hot zones.)



IS THERE A TREATMENT FOR SOMETHING LIKE ROSALIA HEMORRHAGIC FEVER?

So far, there are really only two kinds of treatment for any viral hemorrhagic fever, and that is anti-viral medication and antibody serum. Antibiotics don't treat viral illnesses. (And should not be used unless the infection is confirmed to be bacterial. Overuse and misuse of antibiotics are one reason why drug-resistant bacteria are starting to appear!) Ribavirin and Interferon, common antivirals used in treatments of viral hemorrhagic fevers, don't have any affect on either Ebola or Marburg, so they probably wouldn't with Rosalia either.

Antibody serum are usually taken from surviving patients, or developed in a laboratory beforehand. They are specialized antigens that are made to fight off a specific pathogen; because different viruses have several different types of proteins, antibodies usually can't fight a different virus unless they are extremely similar. In most patients that die, their bodies were not able to create, or create enough of, the antibody needed to fight the virus. The serum sounds pretty helpful, doesn't it? Fortunately, antibody infusion seems to work very well with Rosalia!

Otherwise, treatment is mostly supportive. Intravenous fluids, blood transfusions, oxygen (intubation if severe enough), and the like. Intensive supportive treatment helps the patient survive longer than without, so with good care, the patient may have a couple or so more days, which is a couple or so days more to receive antibody serum. It also depends on the patient himself or herself: a patient with a strong constitution might live longer or have a better chance than a patient with a weaker constitution. And, of course, there are very likely some patients that were able to build up an efficient antibody response, so not all hope is lost even without the serum!