University of Washington Department of Health Services Emergence from Animals and Birds: BSE and Avian Influenza

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INDEX Introduction Canine Parvovirus Viral Hemorrhagic Disease in Rabbits Canine Distemper Finch Conjunctivitis Equine Morbillivirus Bovine Spongiform Encephalopathy (BSE) Transmissible Spongiform Encephalopathies Transmissible Mink Encephalopathy (TME) Chronic Wasting Disease in Elk The Case of Kuru in New Guinea Gerstmann-Straussler-Scheinker syndrome (GSS) Spontaneous Creutzfeldt-Jacob Disease (CJD) BSE-the Case in the United Kingdom What are the manifestations of BSE? Types of BSE Transmissions Control Measure for BSE? Creutzfeldt-Jacob disease and BSE: Avian Influenza Hong Kong H5N1 Wrapping Up Disease Transmission Across Species Boundaries Technology and Xenotransplantation: Example of Pig Transplants Readings INTRODUCTION Expect the Unexpected I know that you have reviewed the factors that are important in emerging human diseases. There is only one factor that is significantly modified for veterinary medicine. In human medicine, this is referred to as lifestyle changes, in veterinary medicine we call it husbandry changes. When you think about diseases crossing species boundaries, and you think about diseases that go into humans from animal species, the possibilities of crossing species boundaries amplifies geometrically. Different animal species are often in close contact with one another, and there is great opportunity for sharing flora and fauna pathogens. SPECIFIC DISEASES Canine parvovirus Canine parvovirus is probably the most famous example we have in veterinary medicine. Anyone who has a dog knows about canine parvovirus. If you don't vaccinate your dog, that dog will die of an overwhelming hemorrhagic gastroenteritis. It was a brand new disease to the world in 1978. It came from the virus of another carnivore, probably the gray fox.   Viral Hemorrhagic Diseaase in Rabbits This is a brand new virus, a calicivirus. It was first described in China in 1984. They think this disease of rabbits came from a European brown hare virus, which is a calicivirus. They believe someone injected this virus into rabbits and it became quickly adapted and virulent for rabbits. There were a million laboratory rabbits in China that died of this disease in 1984. It essentially wiped out all of their biomedical research. It has spread to other parts of the world and is now well established in Europe. In 1988, this virus came to Mexico in a shipment of rabbit meat originating in China. It came through Los Angeles, and then by land down to Mexico City and was unloaded at one of the large grocery stores in Mexico City. One of the butchers from the store worked with this material, he went home and petted his pet rabbit, and gave this viral hemorrhagic disease to his rabbit. This virus than spread throughout Mexico. It has now been eradicated from Mexico. The closest place that we have this virus is in Cuba. VIRAL HEMORRHAGIC DISEASE Species Susceptibility Oryctolagus yes Sylvilagus no Lepus no These are the species that are affected by viral hemorrhagic disease. It only affects rabbits of the Oryctolagus genus. What kind of rabbits are pet rabbits? They are Oryctolagus, as are laboratory rabbits. These are the Old World rabbits. Wild rabbits in the Old World (Europe, Africa, and Asia) and all the domestic laboratory rabbits, are Oryctologus. What are the cottontails, the bunny rabbits? They are Sylvilagus, and they are not susceptible. Neither are the hares susceptible. If we got this disease in the US, it would not affect the wildlife, only the domestic rabbits. The problem in Europe was that it also got into the wild animals. It decimated the wild rabbit populations, which has reverberating ecological consequences. For example, there were decreases in the raptor populations, which feed off these wild rabbits. Rabbit Crisis in Australia Are any of you familiar with this story about what happened with Viral Hemorrhagic Disease in Australia? The Oryctologus rabbits were imported into Australia 150 years ago, and have proliferated throughout the country, to the point where they are serious pests. They eat all the grass, so there is not enough grass for the native animals or for the pastured animals. They are also displacing a lot of the native marsupials. They are an ecological and an economic problem. One attempt to reduce the rabbit population was by introducing myxomatosis virus into Australia. Unfortunately this allowed proliferation of the rabbits that had resistance to this virus. So the Australians decided that this Viral Hemorrhagic Disease of rabbits (VHDR) might be the perfect solution to their rabbit problem. It would kill the rabbits quickly so they would not develop resistance. They did all of the experiments necessary to show that this virus would not damage their native marsupials, and none were susceptible. Then they started their field trials on Wardang Island, an island about 2 kilometers off south Australia. They put the experimental rabbits in a pen and gave them the virus, and all the rabbits died. Then they noticed that the rabbits just outside the pens were dying as well as other rabbits on the island. Within a matter of days, rabbits in southern Australia's mainland started dying. Before long, this virus was all over Australia, causing a lot of rabbit deaths. It was essentially a premature release of the virus. Now what has happened is that many of the rabbit populations have been decimated, and the flora and fauna of the region are returning, but not uniformly.   Canine Distemper Another disease, which has crossed species boundaries, has been canine distemper which was found in the lions of the Serengeti. Canine distemper does not normally infect cats, but it has become a big problem in the Serengeti where they have lost about 1/3 of their lions. How has this disease crossed species boundaries? We believe it is due to crowding at the edge of the park. There are more people and more dogs, and the dogs are getting closer to the hyenas which go between people and the lions in the middle of the park. The virus went from the domestic dogs to the hyenas to the lions. What really worries me is what if this had happened to the rhinos? There are only 39 rhinos left in the Masai Mara Park in southern Kenya. It could mean the end of a species.   Finch Conjunctivitis This is another disease that has crossed species boundaries. House finches are birds that are commonly seen around bird feeders. Many of them are dying along the eastern coast from a blinding Mycoplasma conjunctivitis. The conjunctivitis is caused by Mycoplasma gallisepticum. Now Mycoplasma gallisepticum is normally a pathogen of chickens. It doesn't cause conjunctivitis in chickens. It causes upper respiratory problems and decreased productivity. There are so many finches now that some finches feed around the poultry houses, where they picked up Mycoplasma gallisepticum. There is the possibility that it will spread to other species. It has been seen in some gold finches and blue jays.   Equine Morbillivirus Equine morbillivirus is another virus that has crossed species boundaries. This is a virus that appeared in Australia in 1994. There was a barn full of racehorses, this disease came in and killed 13 horses, and one trainer who was treating the horses. The Australians initiated an intense investigation into the cause of this outbreak. What the Australians found was a new morbillivirus, something that no one had seen before. Another Equine Morbillivirus Appears In October 1995, a person in Mackay, Queensland, developed a serious central nervous system disease and was in a coma. The clinicians decided to test his cerebra spinal fluid for equine morbillivirus and the result was strongly positive. A year before he was hospitalized, he had helped his wife, who was a veterinarian, do a post-mortem examination on two horses that died of overwhelming pulmonary edema, just like the horses in Brisbane. Unfortunately, the cases were misdiagnosed as avocado poisoning. They pulled those paraffin blocks out of storage and did a polymerase chain reaction (PCR) on them and found that the horses did in fact die of equine morbillivirus. We know this virus affects both horses and humans. Finding a Wildlife Reservoir for Equine Morbillivirus When they looked for the wildlife reservoir of the morbillivirus they initially came up empty handed. However, in the second outbreak they started looking at fruit bats. They found 7% seropositivity for equine morbillivirus in these bats. It has recently been found that the virus is shed in the uterine secretions at the time of birth. It causes no disease in the bat. These bats are not indoor bats, they are outdoor bats. Somehow the uterine secretions either fall on the grass or elsewhere but no one knows how the transmission of the disease occurs. Bovine Spongiform Encephalopathy (BSE)   We are going to talk about Bovine Spongiform Encephalopathy (BSE) and its variant, new variant Creutzfeldt-Jacob disease (nvCJD). It is a disease that causes holes to form in the brain. It's a spongiform encephalopathy. All of the transmissible spongiform encephalopathies are caused by prions. Prions are proteinacious molecules that cause disease. Stanley Prusiner is the one who coined this term prions in his 1982 Science article. What are prions? They are little infectious particles of an altered form of normal protein found in the brain. What do these prions do? Once they are formed in the brain they come up next to one of the normal proteins and induce that normal protein to change. Then that abnormal protein induces another normal protein to change. The normal prion proteins, which we all have on the cell surface of our neurons, are easily degraded and there is constant turnover. When these prions become abnormal, they do not get degraded, so they accumulate. They actually accumulate in the endoplasmic reticulum. They make the cell swell, and create these holes in the brain that interfere with the normal functioning of the neurons. Prions are referred to as both normal and abnormal, so this PrPc is the prion protein control. That is normal. Then the PrPsc is for prion protein scrapie is the abnormal one. It is also referred to as PRP-Sen because it is sensitive to degradation and PrPres because it is resistant to degradation. Transmissible Spongiform Encephalopathies humans: kuru, GSS, FFI, CJD sheep/goats: scrapie mink: TME elk/deer: chronic wasting disease cattle: BSE What are the transmissible spongiform encephalopathies? The first one that was described is the one in sheep, called scrapie. Scrapie has been described as far back as the 1700's. The transmissibility of scrapie was confirmed in the 1930's when a vaccine was made from sheep brain. They inoculated 2,000 sheep with this vaccine and they all came down with scrapie. Therefore we have known that scrapie is a transmissible disease There are only two countries in the world that are free of scrapie, Australia and New Zealand. The United Kingdom has a very high incidence of scrapie. One to 2% of their national herd of sheep get scrapie every year. Transmissible Mink Encephalopathy (TME) Transmissible mink encephalopathy (TME) was described in the 1950's. A researcher, Dick Marsh believed that TME is proof we have BSE in this country. Mink were fed downer cows. Do you know what downer cows are? When you have an animal that is down and cannot get up, you automatically send them to the slaughterhouse and they are turned into hamburger. Since mink are fed downer cows, and the mink came down with TME, then we must have spongiform encephalopathy in cattle here in the US. A second hypothesis is that there is very low level of spontaneous spongiform encephalopathy in cattle in this country and that is not the same as the BSE seen in England. Chronic Wasting Disease in Elk In Colorado and Wyoming, 5% of the deer population have a condition called chronic wasting disease. This was first discovered in 1979 in captive elk. Now we have it in wild elk and mule deer. The Case of Kuru in New Guinea The first transmissible spongiform encephalopathy in humans was Kuru. It was a progressive neurologic disease, which killed the person affected. The name is taken from one of the signs of the disease, trembling. In the 1950's, Carlton Gajdusek studied this disease and found it among the Fore tribe in Papua New Guinea, a tribe that practiced cannibalism. He did not know if it was a toxic, genetic, or infectious disease. Bill Hadlow, a USDA scientist working on scrapie, became aware of Gajdusek's studies and commented on the similarity between scrapie brain samples and kuru brain specimens. This stimulated Gajdusek to explore the possibility of kuru being an infectious and transmissible disease. He found that the disease was transmitted through the cannibalistic rituals, especially those who ate the brains were most affected. Laboratory research in this area confirmed the initial theories. Gerstmann-Straussler-Scheinker syndrome (GSS) This is one of the other spongiform encephalopathies in humans. It is genetic and transmitted in an autosomal dominant pattern. It is a rare disease. If they are genetic then why are they classified under transmissible diseases? The genetic programming can switch that normal prion into an abnormal prion, but if you take material from an infected person and put it into another human, they will get an encephalopathy. How does that happen? This has occurred in approximately 60 case through dura mater transplants. A second route of transmission has been through use of pituitary growth hormone, when they used material from human pituitary glands. There are about 90 cases worldwide, mostly in children, where pituitary growth hormone was inoculated into children who were of short stature. Spontaneous Creutzfeldt-Jacob Disease (CJD) Creutzfeldt-Jacob disease is a sporadic, progressive, fatal degenerative disease of the brain. It presents with signs of dementia, incoordination, and seizures and has been known for several decades. The new variant-Creutzfeldt-Jacob disease is similar in its presentation but appears to be linked to ingesting animal products, particularly beef, infected with bovine spongiform encephalopathy (BSE). BSE-the Case in the United Kingdom This is a new disease to the world. We saw the first case in cattle in 1985 and diagnosed in 1987. In 1988 it became a reportable disease. [Slide] In 1992 there were over 35,000 cases. They looked very closely at all of the animal husbandry conditions of the cattle. In particular, the rendering process was suspected. During this process the cattle come down the slaughter line and all the best meat is removed for marketing to humans. What remains of the carcass is "rendered" or ground up and turned into meat and bone meal. Meat and bone meal is used for cat and dog food, as part of the feed to cattle, and for gardening. During this process, tallow was extracted which is used to make soap and pharmaceuticals. To extract tallow requires a solvent and heat extraction which likely removed the infectious agent of BSE. In 1981, the market for tallow diminished and in the United Kingdom they stopped the solvent extraction when making the meat and bone meal. It is hypothesized that this contributed to the rise of BSE in the United Kingdom. There was likely low level of BSE in cattle which became magnified by the animal husbandry practices of feeding meat and bone meal to cattle. The question, which has not yet been answered, where did the prion agent come from initially? [Student question: How long have we been feeding animals meat and bone meal?] This type of practice began in the 18th century and is a result of the industrialization of the cattle business. Bones were taken from the carcasses, and ground into powder and then fed back to the cattle. It was an efficient use of resources. This is the technology that was created as a way to feed world populations. What are the manifestations of BSE? First, the disease has a long incubation period, anywhere from 6 months to 5 years, before clinical signs appear. The trigeminal areas of the brain is affected causing twitching. They lose coordination, balance and strength. They become ataxic and very nervous. Eventually, they become "downer" cows. Examining the histopathology of the brain looking for the characteristic vacuoles in the brain makes diagnosis. There is no screening test available to diagnose this condition before the clinical manifestations. The diagnosis is usually made at post mortem examination. In the United Kingdom, any central nervous system in cattle is considered to be BSE until proven otherwise. The affected cow is then slaughtered and the diagnosis made. When the outbreak first began, Russia was having terrible problems with lack of food, and the United Kingdom offered to send all of their BSE positive cattle to Russia. The UK also offered to send cows to Cambodia because they have problems with land mines, and they were going to send the cows through the countryside to find the land mines. Unfortunately, a great deal of this meat was smuggled out of the UK and distributed throughout Europe. The Nature of the Prion in the Lymphoid System Newer studies have shown that the prion first invades the lymphoid system via the terminal ilium, in cattle. It was also found in the bone marrow and nervous tissue. Therefore, it is possible for infected portions of the carcass to get into food products, especially hamburger. [Question: Is it possible to deactivate the scrapie agent?] Scrapie can survive even after putting it into the autoclave for 2 hours on high heat. Heat does not seem to kill the infectious particle, neither do many commercial bleach products etc. In other words, it is not easily deactivated. The End Result and Diagnosis of Spongiform Encephalopathy The end result is holes in the brain which severely impairs nervous function. This shows the area of the brain where the diagnosis can be made. There is a newer test using immunohistochemistry to look for the altered prion protein. In the United States, we have examined over 6000 cattle brains and have not detected this disease. Types of BSE Transmissions This slide shows some of the results of experiments in transferring infectious material from one species to another. Here is a diagram of the areas that are effective for transmission. We can add bone marrow to that. Control Measure for BSE? There have been over 170,000 cases in the world, most of which have been in the United Kingdom. Many countries have had experience with the disease as a result of importing British cattle, usually as calves, and then as they become adults, they manifest the disease. There has been one of case in Alberta, Canada. Belgium, Luxembourg and the Netherlands have all declared cases just within the last year, and it is thought that all of these cases are due to feeding meat and bone meal that came from the United Kingdom. [Question: You showed an epidemic curve, but how sure are we that it did not appear earlier in British history without diagnosis.] Well, it would not have been a problem of epidemic proportions before, or we would have seen it, because dairy cows live a long time. Once they have developed CNS signs, they are no good. It would have been a problem of economic proportions. But we really did not see the disease before 1985, so I think it has only been a problem since then. Now interestingly, the disease was declared in the United Kingdom in 1987. We did not stop importing cattle from the United Kingdom until 1989, and we had about 500 cattle in the US of British origin when we really started to go after them. [Question: Even though we stopped importing cattle in 1989, what about the meat and bone meal?] The specified bovine offals-we did not stop importing immediately. However, bovine products are used in numerous pharmaceutical producst, cosmetics, shoe and floor polish, and candles, to name a few. A whole nation of beef eaters had to change their ways. This gives an idea of the number of brains that have been examined in the US. Of close to 500 cattle were imported into the US prior to 1989, there are only 17 left. We have tried to buy all of them and kill them and examine their brains, but these few left have just become incredibly expensive. USDA has decided, well, we'll just send an inspector out there once a week to make sure that cow does not go anywhere. That would be cheaper We mentioned about this smuggled British beef. At least 10,000 tons of British beef have been sold to the European continent. Creutzfeldt-Jacob disease and BSE: Are they the same agent? In October 1997 there were two articles in Nature that essentially sealed the fate of BSE being linked positively to new variant Creutzfeldt-Jacob disease. They did research to show that yes, these are in fact the same agents. There have only been 23 cases of new variant Creutzfeldt-Jacob, however it is expected that there may be between 100 and 1,500 human cases in total. Differences in Variations of Creutzfeldt-Jacob disease nvCJD CJD Age young old Disease course prolonged rapid Clinical disease behavioral changes dementia Prp plaques frequent infrequent Differences between new variant Creutzfeldt-Jacob disease and the sporadic Creutzfeld-Jacob disease are obvious. Sporadic CJD usually affects older people, 60-70 years, whereas in new variant CJD there are teenagers or young adults who are affected. The mean age of death for nvCJD is 28 years old. It has a long incubation time and disease course. The presenting signs are psychiatric and behavioral changes, many patients are initially treated by psychologists and psychiatrists. The histology of the brain is also different. In the new variant Creutzfeldt-Jacob disease, there are many amyloid plaques throughout the brain which is not present in the sporadic form of the disease. [Question: Are people still feeding ruminants the meat and bone meal?] Most places in the world are no longer feeding ruminant meat and bone meal to ruminants. The carcasses have to be burned now, so we may see some environmental consequences of getting rid of the extra ruminant material. [Question: What about the United States?] We banned the feeding of sheep and goat meat and bone meal to cattle when the BSE outbreak started in 1989. We banned the feeding of ruminant meat and bone meal, it was a voluntary ban that lasted three or four years, now I believe it is a mandatory ban. It is costing us a lot of money, because now in our post-mortem room, we now have to burn all of those carcasses. They cannot go for dog food anymore, and it costs about $1 per pound to burn, so you are talking about a few 500 pound cows per week, it is expensive, and there are going to be people who try to find their way around regulations because of economics. Avian Influenza We will talk briefly about the highly pathogenic avian influenza. We had a big outbreak of highly pathogenic avian influenza in birds in the United States in 1983 and 1984. We killed 17 million birds to control it. It cost the US $63 million to eradicate it. An economic study was done, and found that if we did not eradicate it, over the course of a year, US consumers would pay another $5 billion for poultry products and eggs. How did it get into the US? We see highly pathogenic avian influenza around the world periodically. We know that there are a lot of high pathogenic strains out there that will cause disease, but this particular virus was strange. This virus came from ducks. It was an avirulent virus until there was a single point mutation that caused the whole virus to become virulent. This was a spontaneous genetic mutation. It arose right here in the US. Influenza viruses are all part of the orthomyxoviridae family, their hemagglutinin and their neuraminadases, the H and the N gene characterize them. Hong Kong H5N1 Virtually all of the highly pathogenic avian influenza strains are either H5 or H7. That big one that we had in Pennsylvania in 1983 and 84 that killed 7 million chickens, that was H5N2. To classify a virus as highly pathogenic, means that it causes a lot of mortality in chickens. These viruses usually have a very short incubation period. The birds tend to have these very swollen wattles or combs, with edema of the head. They may have hemorrhage along their shanks, and then they die. They are usually dead within three to four days. The pathogenesis of this strain H5N2 is identical to the pathogenesis of the Hong Kong strain H5N1. The most characteristic finding is edema around the head. How Does It Kill Them?   Initially the respiratory epithelium is infected, from there it spreads to the blood vessels. Once in the blood vessels, the capillaries throughout the body become infected. Within 24-48 hours the virus has multiplied enough to cause capillary leakage and bursting throughout the body. In can cause necrosis of the brain and the heart. This is very similar to the large influenza epidemic in 1918. How Is It Transmitted? It is an airborne virus that appears to be transmitted from waterfowl, i.e. ducks, to chickens. The ducks are usually not affected by the virus. The waterfowl migrate and spread the disease where they go. The majority of serious influenza diseases is usually due to chicken and pig influenza viruses mixing with the human influenza strains. This is how most of the influenza epidemics start, 1968 Hong Kong flu, 1976 Swine flu, and the 1918 flu. How Does This Relate to the Hong Kong outbreak? There has never been a case of avian influenza getting into humans and causing disease before. There have been several cases of swine influenza that have gotten into humans and caused limited person transmission, but this avian influenza is a first. Of the 18 cases in humans, there have been 6 fatalities. This is a bad flu. In order to control the outbreak, Hong Kong authorities decided to kill all the chickens. Over 1.6 million chickens were slaughtered within 2 days. Some of the transmission may have occurred due to the practices in the live animal markets where ducks, geese and chickens cohabitate thereby allowing transmission to occur. They have shown that this particular H5N1 strain is in the geese and the ducks also. The potential for further spread among the waterfowl and the chickens continues to exist. [Question: Is someone trying to correlate the migration of certain types of water fowl with these problems?] I think the only people who are working on that are the USDA at the Southeast Poultry Research Lab. Wrapping Up Disease Transmission Across Species Boundaries Crossing species boundaries domestication zoological collections population pressures eco-tourisem I think that the possibilities for disease transmission through this avenue are only increasing. We are domesticating a lot more species than ever, we are mixing species together. Our zoological collections, we are continually mixing species from different parts of the world, maybe species that are not evolutionarily compatible with one another. Population pressures in the world are absolutely unrelenting. We are close to 6 billion people in the world. Everybody has to have a place to work, place to play, place to live, and we are just really pressing the environment. Ecotourism where a lot of people are going to remote areas to view endangered species. This is very good for the local economy, and it increases the visibility of these species, but how long will it be before we take measles or influenza or rhinoviruses to these groups that are really very immunologically privileged. The reverse is also possible where humans may be exposed to potentially dangerous viruses from the wildlife. Technology and Xenotransplantation: Example of Pig Transplants Xenotransplantation is one of the best examples of biotechnology and potential for cross species infections. One can take hearts and kidneys from a genetically altered pig and put them into humans. We have to draft protocols for how to insure that these pigs are free of any diseases that might go into humans. How about if you took a person with a heart lung transplant, and they got swine influenza that then mixed with their human influenza and started a big outbreak. Talk about the perfect place to produce brand new diseases. But these transplant surgeons had no idea. Readings: Nathanson N, Wilesmith J, Griot C. "Bovine Spongiform Encephalopathy (BSE): Causes and Consequences of a Common Source Epidemic". American Journal of Epidemiology, Vol. 145, No. 11, 1997, pp. 959-969. Return to Title Page HOME  |  List of Lectures