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But treated at the early influenza stage, feeling like -- yeah, they respond beautifully. Once it's got to the systemic infection stage, there is nothing you can do for them. They die.

Next, please.

In the old days, this is one of Phil's photographs. This young man feeding wool into the hopper for work, and there would be tremendous amounts of spores in the air, high risk. This is why it was known as Bradford disease, from Bradford in England, which were wool mills.

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Gastroenteric. It's seen -- at the moment, it's largely seen in Central Asia and in Africa. It comes from eating an animal that's died of or with anthrax, nausea, malaise, abdominal pain, bloody vomiting, diarrhea. Carries about a 30 to 40 percent case fatality risk.

Next, please.

This is an animal that I photographed being butchered outside a village in Somalia. In Africa, people may eat meat only once in six months, once a year. So they'll risk it.

The better the cook, the more likely you are to die of gastroenteric anthrax. The worse the cook, in other words, the more the meat is cooked, the safer it is for everybody, and we worked it out, Peter Turnbull and I. It's basically about one in 67 anthrax livestock cooked which results in gastroenteric cases. It's at that level of risk.

And for them, if you've got malnutrition, it's worth taking the risk.

You'll also find cutaneous lesions in those people who are butchering the affected animal.

Next please.

This is the most recent map we have for the disease. The areas in red are where it is hyperendemic. Brown is where it is endemic. Yellow is sporadic. There are a few countries, areas where it is free, like in Malaysia, Taiwan, Norway, Finland, the Guyanas, Egypt apparently.

But in Europe it is, in fact, disappearing, and I think in a few more years we can start coloring in Europe as probably free.

In the United States it's endemic in Southwest Texas and in the Dakotas. In Canada, Alberta, Saskatchewan, and the southern part of the Northwest Territories, they get cases regularly up there each year, but the rest of the United States it's very infrequent to say the least.

I could take you to places where it might occur, but it has, in fact, disappeared beautifully in North America, and we'll just be left with these few areas where there are problems.

Next.


Okay. Sverdlovsk. In 1979, there was a  - from what we can make out, they were grinding some weapon fill, and the outgoing team found that the filters were clogged, and they left a note for the incoming team that they'd taken the filters out, and they'd better replace them with clean ones before they started up.

Again, they didn't read the note, and they started grinding this weapon fill.

The work we did on some tissue from these people indicated that minimum of at least five strains were involved. In fact, we've now been informed that six strains were involved in the Russian weapon mixture.

The number of people who died is probably in the region of 90. The reason we say that is that some early cases were missed. The military cases were definitely not revealed. The Russians said they had 64 cases because that was the number of pensions they were willing to pay, and there was a certain amount of musical chairs involved. If somebody was confirmed not to have had anthrax, they were taken off, and somebody came in and got a pension.

But we reckon somewhere around 90 people died. How many people became ill is any number you care to think of between 120 and 400. They initially reported as due to contaminated meat, which they insisted on for many years.

The local team diagnosed the first case as anthrax on the 10th of April by Faina Abramova and David will tell you about the story with that.

The local team did a very good job, but they missed the original cases. I've forgotten. The first man to be diagnosed was what, number 12 or number 20-something, Markhov. He wasn't the first one. That's for sure.

And the level -- there was a constant wind from the northwest at the time of the release, and calculations that I've been involved in, based on exact time of exposure of the people concerned, indicated some half a kilo of spores were released.

The exposure from people I measured who were living inside the plume and working outside or working outside and -- sorry -- living outside and working inside the plume or having to cross the plume in some way or another indicated that release was between 6:15 to 7:45. So it was quite a prolonged period of exposure. It was not one puff that went by and you had to be standing outside and take a deep breath. It was out for quite a while, and this is why there was so much.

And it killed animals where you see the letters of the alphabet, and the furthest out was some sheep who certainly would have died from the aerosol 53 kilometers out. The furthest human case was 4.3 kilometers.

Next, please.

Going over the records, which we did have, a very interesting thing comes out of this. Now, there are all sorts of problems with the database, but just we'll take what we've got, is that normally you would have a normal Gaussian distribution for onsets, but it starts collapsing on the 15th of April, and then we just get sporadic cases.

Next, please.

The deaths stopped on the 16th, after which there were sporadic cases.

If we overlap the two -- next, please -- we get this pattern, and I went back over my notes, and I checked with Alex Shelakov, who was with us, and we both were told that, yes, people were taking oral antibiotics.

The normal routine was when the medical team when to the household where a case was, is the family was prescribed oral antibiotics, and Olga Yampolskaya, who was with us, who had been on the original Moscow team that came down on or around the 11th or 12th of April, she said, yes, they were on oral antibiotics, but there was a community-wide prescription on the 15th of April.

I then checked with my colleague in Moscow, Benjamin Cherkosskij, who is a long time colleague of General Burgasov and had been involved with him in the vaccine trials in the Ukraine in the '70s when they vaccinated three million people. He said, yes, at the time they had a laid down procedure for five days of antibiotics, which confirmed what Olga had said, and the drugs were ampicillin, tetramycin (phonetic).

I'm afraid I prepared a special slide for this, but it seems that academia has better computers than FDA, and they can't read my version of Power Point, but I'll make sure you get a copy of exactly what these drugs were and their protocols, but it was once or twice a day. They were penicillin derivatives or tetramycin.

Next, please.

Something else you've got to keep in mind is that we had these addresses of these people. The compound wall was 900 meters from the source, and it was three stories high, and there was a constant wind for quite a number of hours, and you can see that the residences where people were living who got sick and died are not evenly distributed.

Next, please.

If you take where people were working, similarly that bit about 25 to 27 meters -- 2,700 meters is where the ceramics factory was, which is where the majority of people died.

Next.

And if you put the two together, it comes out that we have a periodicity of 900 meters. In other words, we have a leewave (phonetic) formed by the wall of the compound. A leewave is just one that does literally this. If you're a glider, you'll know exactly what I mean.



And so as it hit, if you were in part of the town where it hit, that's where you were at risk. Otherwise you weren't.

We had confirmation on this one in talking to the locals where they said, "Yes, nobody died in our street, but they did in the street over." So it's different.

Next, please.

I'm involved in a very large study, as I said, in looking at the molecular biology of this bargain, the molecular epidemiology. It is a large collection, and we recently took receipt of the Italian national archive and, along with other Italian isolates we have, it comes to about 53. They're essentially from Rome and Sardinia south.

And in preparing the DNA for this, we now routinely make archival preparations, and in the first time my graduate students responsible for this noticed that we had three that were gammaphage resistant.

Normally, in the screening of this organism in culture, you look for organisms which are penicillin sensitive and are gammaphage sensitive. Now, these were penicillin sensitive, but they were gammaphage resistant, something we hadn't seen before. It's in the literature. We were expecting it to happen, and so she said, "Well, let's try out a whole range of antibiotics," which is something we hadn't done before. We had ordered it, but we had never done whole range.

And lo and behold, the Sample A, 850 up at the top there, was resistant to ciprofloxacin. This was a goat that died in '96 in Sicily, and that's essentially all we know, but as friends of mine say, if you give antibiotics to sheep and goats, you've doubled their value. So they tend not to be treated all that much.

Sheep and goats are, in general, I'm sorry to say as a veterinarian, are under treated, under cared for by their owners as opposed to cattle who sometimes get far too much treatment.

Kudu '93 at the bottom is our standard strain out of the Kruger National Park. It is the commonest strain in that park, and so that we put up against it.

And so what I'm trying to point out to you is this. This is the first time we tried out any other drugs than penicillin, and in the first attempt we stumbled on this ciprofloxacin resistant isolate. We have no idea of how common it is at all. I had no idea how commonly ciprofloxacin is given to livestock. In my experience not at all, but people from Bayer can tell you what their veterinary sales of this drug are.

Thank you.

CHAIRMAN RELLER: Are there questions from the panel for Dr. Hugh-Jones? Yes, Dr. Chesney.

DR. CHESNEY: We were wondering what the numbers represented. Are those number of strains or MICs in the table, the last table?

DR. HUGH-JONES: The last table? No, the numbers was the distance from the edge of the paper disk to where the lawn started growing again.

CHAIRMAN RELLER: Dr. Hugh-Jones, has the strain that you found resistant by disk testing --

DR. HUGH-JONES: Yes.

CHAIRMAN RELLER: -- has that been confirmed at a reference laboratory by dilutional MIC, agar dilution, other measures?

DR. HUGH-JONES: We only discovered it a few weeks ago. It hasn't been passed on for MIC testing.

CHAIRMAN RELLER: I'd like to encourage that. I mean, there are a lot of pitfalls with the disk testing. In concert, I know that recently in the National Committee for Clinical Laboratory Standards has published the susceptibility guidelines for veterinary medicine that are cross-linked with those for human.

But very important in that as a general comment is in newly recognized phenomena of potential public veterinary health interest and importance of reference laboratories of confirming the mechanism and degree of resistance. So that would be very helpful, I think.

DR. HUGH-JONES: I would agree with you. We hadn't expected it, and suddenly it was there, and now we've got to think about, okay, if we set up MIC testing, how much and who pays.

CHAIRMAN RELLER: Right. I'm sure the CDC would be delighted to work with this, Dr. Tenover and colleagues.

Other questions from the panel for Dr. Hugh-Jones?

And, again, all of the consultants, speakers will be available later at the time of the public discussions for further -- yes, Dr. Friedlander.

DR. FRIEDLANDER: Yes. Just a comment about this. I noticed that several of the strains were resistant to vancomycin.

DR. HUGH-JONES: And variably so, and I don't understand it.

DR. FRIEDLANDER: I mean that would be, at least in our experience, and I believe in the literature as well, almost all the strains as sensitive to vancomycin.

DR. HUGH-JONES: Yeah.

DR. FRIEDLANDER: So further reason to look at these, I think, carefully.

DR. HUGH-JONES: Yes.

DR. FRIEDLANDER: It may be something different about these strains. Have they been tested for virulence in animals? Do you know?

DR. HUGH-JONES: These are all from clinical field cases.

DR. FRIEDLANDER: I understand that, but have they been reconfirmed in terms of their virulence for mouse?

DR. HUGH-JONES: I have only a limited amount of research money, Colonel Friedlander. I'm not funded by the DOD for such experiments, which are not inexpensive, I may add.

COL. TAKAFUJI: Colonel Takafuji.

Could you make some comments about the mode of resistance, chromosomal mediated, plasmid mediated resistance and the implications thereof here?

DR. HUGH-JONES: Well, the little I know about the ciprofloxacin resistance in anthracis is frequency is about five times ten to the minus nine. It's chromosomally based. It has nothing to do with the plasmids.

There are further genes involved if you then challenge the organism against higher and higher doses of ciprofloxacin. These have been defined for modest increases of ciprofloxacin, but not for the highest levels.

There's been very little work done really in the genetics of it.

CHAIRMAN RELLER: Dr. Archer.

DR. ARCHER: Do we know that if spores exposed to an antibiotic for a period of time can develop resistance before they germinate into vegetative cells?

DR. HUGH-JONES: No reason why they should. The spores are just dormant. They're susceptible to disinfectants. That's how you get rid of them.

CHAIRMAN RELLER: Dr. Friedlander.

DR. FRIEDLANDER: If I might address that, I don't think there's any evidence that anything works on the spore per se, but the antibiotics do work very quickly in the early germination of the organism. I mean, if you look at the organism, you basically can prevent the development to the Bacillus. It works very quickly, as soon as uptake starts probably.

DR. HUGH-JONES: I mean, at field decontamination you can get a hell of a long way just with a hose and water, believe it or not, but once it sporulates, it's much more resistant.

DR. ARCHER: So with a relatively low inoculum of persistent spores, for instance, there's no reason to think that chromosomally mutant vegetative cells would develop during the course of prophylaxis if they're not resistant to begin with.

DR. FRIEDLANDER: Right. There should not be a significant multiplication going on.

DR. HUGH-JONES: The evidence that we've seen so far is that when you expose it to antibiotics, you're just finding those one or two on a plate which are resistant already. They had it before they started.

CHAIRMAN RELLER: Yes, Dr. Christie.

DR. CHRISTIE-SAMUELS: In the outbreak, do you have any more recent information as to why there were no children involved?

DR. HUGH-JONES: The only reason I can think is that the exposure dose was really rather small, and what we were seeing was people with industrial, occupational damage with ongoing like welder's lung, poor clearances.

The youngest person that died was 26, but she every morning went and took a shower at the ceramics factory, and that was a hit point. Where her day care center was was not. So I think she got it by walking into it.

There was a young teenager who was reported ill, treated, and recovered, but that's all we know. There were a couple of teenagers, but none died, and it was a puzzlement with us as to why we had so few, well, virtually nobody under the age of 40.

There was a question from the commandant over here.

PARTICIPANT: That was my question.

DR. HUGH-JONES: Oh.

CHAIRMAN RELLER: Thank you again very much.

And now Dr. David Walker will present the human pathology of inhalational disease with Bacillus anthracis.

DR. WALKER: The purpose of my presentation is to show you what the inhalational anthrax does to humans, and the first part here is merely an excerpt from Alibek's book in which he gives a second hand version of what the exposure was, which Martin Hugh-Jones has just told you about.

And so I'm going to move directly to presenting to you the quantitative pathology of inhalational anthrax.

The most important person here is Dr. Abramova, who was a senior pathologist in Sverdlovsk. She made the first diagnosis that was made. She is a pathologist, and she recognized the hemorrhagic meningitis as being likely due to anthrax, assimilated anthrax in the first autopsy that she did, and she confirmed that by making smears of the brain, seeing Gram positive bacilli, and cultivating the amount with cultures available the next day.

And they went on to do autopsies on all of the patients that came through during that period of time.

A resident in pathology, her protegee at that time, Dr. Grinberg, participated in all of those autopsies. He subsequently came to my department, brought the material to the United States, and we have studied it further, and what I will be showing you are the results of those, some of the results of some of those studies.

The pathologist at the University of Texas Medical Branch in Galveston, who is responsible for working with Dr. Grinberg, who produced together the data here, is Dr. Jerome Smith.

I already mentioned to you Olga Yampolskaya was a protegee; an anthrax expert who was sent from Moscow, Dr. Nakiferov. She worked with patients in the intensive care unit. She went down to the morgue and saw the results of the autopsies. She went back and served as a member of our team and translated with me as I worked with the Russians in reviewing the material there.

She also came to the United States during the period that Dr. Grinberg was in my department, and communications help to make the progress in that report occur during that time.

This is Dr. Yampolskaya, Dr. Grinberg, and Dr. Abramova. And there we are at work, and the amazing thing is that although records were -- can we lower the lights a bit here at least in the front of the room? -- the amazing thing is although the KGB came in and took all records, everything that was written, the primary material was maintained, and so the picture here shows us in the morgue actually during my visit there.

And you can see that she actually has saved the organs, and they saved all of the slides, and although written words were destroyed, the primary material was still available.

And this shows some of the brains with hemorrhagic meningitis and the hematogenously disseminated lesions in the gastrointestinal tract, which I'll describe to you and show to you.

And this is an example of what she saw in the first case, and there were many cases that had hemorrhagic meningitis, and this is one of them. So we see the skull cap opened up, and she recognized that. It has a name. It's called the cardinal's cap because of the red color, and it's really a subarachnoid hemorrhage of hematogenous dissemination to the brain, and this is an important part of the pathology in about half of the cases.

Anybody that knows how to work this better than I am, I'll take some lessons.

The key pathology is after the spread of the spores to the thoracic lymph nodes, they germinate, proliferate, secret the toxins, and you get a lot of local damage right there in that area.

So here we see the lungs with the trachea opened up and the bronchi, and all of this very dark material are lymph nodes that have got hemorrhagic necrosis extending out into the mediastinum so that there's actually hemorrhagic mediastinitis, and this is characteristic of the inhalational form of anthrax.

Next.


And it was seen in all of the cases.

Next.


Just to reiterate, here we have opened posteriorally the esophagus, and you can see in the mediastinum the severe hemorrhagic mediastinitis.

Next.


I was very impressed that they had saved this, and this is sitting there in the museum of the medical school with the huge hemorrhagic lymph nodes, and you'll notice that the lungs themselves in this particular case don't show very much pathology at all, but there is severe enlargement, hemorrhage, and necrosis of the tracheal-bronchial lymph nodes.

Next.


I realize that I'm overdoing this, but I'm doing this on purpose just to show you this is consistent, and it's present in every case, and it's really the thing that's most important to prevent.

I think most of the things that lead to patients' death occur in the chest, and this is what the major lesion is. Again, trachea opened up, massive hemorrhagic necrosis of the lymph nodes.

Next slide.

Now, the histology shows a lymph node here with hemorrhage in it and spreading out around into the mediastinal fat.

Next.

Histologically we can see virtual replacement of the lymph node here with hemorrhage, and hemorrhage also extending into the mediastinal fat.



Next.

So hemorrhage is a very important component of what's killing the patient. A lot of sophisticated work, and we're going to hear a lot of correlations from Dr. Friedlander who is really the expert on this subject of how the organism does this, but at the level that I'm looking at it with you, a lot of it is truly mechanical.

Yes, the organisms are there. You can see the Gram stain here. This is a lymph node, the marginal science in which you can see the Gram positive bacilli that have spread and grown in that location and certainly must be producing the toxin.

Next slide.

And the hemorrhage here has been looked at and classified by Dr. Jerome Smith into two categories: a high pressure hemorrhage, which really distorts the surrounding tissue and compresses the structures.

Next slide.

And in these areas of mediastinum where the hemorrhage is occurring, one also finds the Gram positive bacilli.

Next slide.

So the effects clearly are coming from some damage to blood vessels.

The other effect is the effect of edema, edema toxin, a combination of protective antigen plus legal factor, very, very apparent.

And here we see gelatinous edema. This is the rib cage opened up, and we see the lungs here, but the mediastinum is massively swollen by edema, and that's a very gelatinous edema that -- next slide -- shows histologically to be very fibrin rich. So there's a lot of fluid in the interstices between exudates of fibrinogen that had polymerized to form fibrin. So it's a very gelatinous material.

And this also forms the space occupying lesion in the thoracic cavity.

Yes, the next slide.

So in the original publication based upon looking at the slides and the material with the Russians, their slides, their microscopes, and under the conditions that we had, we had 42 cases, and the 42 cases that we felt were anthrax, and this was published in proceedings of the National Academy of Science article, and we showed that many of them were confirmed by culture or confirmed by identification of the organisms histologically.

Next slide.

Subsequently one of the cases that we've taken now, Case No. 24. Case No. 24 was a lady who received eight days of antibiotics. So we didn't find any organisms, and she really had recovered from her disease, and she died of complications.

Her original disease very well could have been anthrax, but we couldn't prove it, and so that case has been removed. So now there are only 41 autopsied cases.

So what are the characteristics of these patients? One of them was a man of unknown identity who was found dead. It was a forensic case. We don't know how old he was. We don't know who he was, and so he's -- n is only 40 for those that we know the age.

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