The Independent (Kampala)

4 November 2012

Uganda: The Marburg Virus Puzzle

Dr Thimm, the man at the centre of isolating the disease, explains why it is happening

Since the ministry of Health declared an outbreak of the viral hemorrhagic fever, Marburg, in Kitumba sub-county in Kabale district on Oct.19, questions have been asked about the real cause, origin and efforts to find treatment for the disease.

Although the Marburg virus was first identified and traced to Uganda in 1967, the latest attack is the third in five years since 2007. It also follows very closely to a July attack of another viral hemorrhagic fever, Ebola, which killed 17 people in Kibaale district in the same region. It was the third Ebola outbreak in five years.

In search of answers about the increasing spate of hemorrhagic fever outbreaks, The Independent spoke to Dr. Bernhard M. Thimm, the German Microbiologist and Epidemiologist who exported the Green Vervet Monkeys (Cercopithecus aetiops) to the Germany city of Marburg in 1967 and sparked the hunt for the virus that continues to this day.

Dr Thimm, now 75 years old, says he first came to Uganda in 1963 after Uganda had got its Independence from Britain and became short of veterinary doctors. He is in Uganda again at the moment where we met him for an interview.

By that time he was a 26-year old PHD holder in Veterinary Medicine and worked at the only Small Animal Clinic in Uganda down at the golf course in Kampala. He was later made District Veterinary Officer for Acholi District in 1964-65, then District Veterinary Officer for Bunyoro District and, after diagnosing a new disease there in cattle (Brucellosis) in 1966, he became the Head of the Disease Investigation Department of the Animal Health Research Centre in Entebbe. This also meant that he was the Veterinary Officer in Charge of the Entebbe Zoo and was, therefore, responsible for the export of wild animals from Uganda from 1967 - 68.

During his work at the Zoo he came in contact with William("Tom")Mann, a nephew of the German Noble prize winner in literature, Thomas Mann.

At that time "Tom" Mann was a well-known, skilled animal catcher and game exporter allover the world. He had received a new order for 300 Green Vervet Monkeys1967 (Cercopithecus aethiops) from Behringwerke Marburg, Germany.

The monkeys were to aid in the production of a measles vaccine using monkey kidney cells. Mann hunted for the green vervet monkeys and kept them in a large group of over 3000 animals on a not inhabited island within Lake Victoria near Entebbe. He would feed them regularly until he collected a batch of 300 green vervet monkeys which were ordered each time.

He brought the veterinary clearance documents to Dr. Thimm for signing after making the necessary optical health check. He said that on visual inspection, the monkeys were healthy and energetic without any wounds in their single compartments.

Dr Thimm signed the export documents and stamped them,and then Mann took them back to the then Ministry of Veterinary Services, Animal Industry, Game and Fisheries for approval. The animals were then exported by air to Behringwerke, Marburg via Frankfurt Airport as many times before.

Dr Thimm says that on arrival the monkeys were put in cages and anaesthetized before being operated to take out the kidneys. The veterinary doctor of the Behringwerke laboratory, his veterinary assistant,and two Laboratory Assistants worked on the animals and the kidney specimens, while a technical cleaner cleaned the tables, the instruments and the floor. The cells of the kidneys were taken out to develop the measles vaccine. "At that time using animal kidney cells to make vaccines was the gold standard," says Dr Thimm.

After only two days of being in contact with the monkeys and the specimens taken from them, Dr.Thimm says the Veterinarian of the Company, his Veterinary Assistant,the technical cleaner, two laboratory assistants, the wife of the Veterinarian and a visiting scientist from Yugoslavia and his wife all got heavy headaches, high fever, vomiting, profuse sweating of blood out of all body openings and through the skin.They all died after a thorough diagnosis and symptomatic treatment in the Intensive care unit of Marburg University Clinics under Professor Dr. Siefarth.

A completely new disease had hit the world:

"Nobody knew what the cause was," says Dr Thimm, "whether it was a bacterium, a virus, a prion, nobody knew anything about it." It received the name 'Marburg Disease Virus'.

The first seven patients who had contracted the suspected virus died within a week. All together 31 patients who had come in contact with these animals from Uganda and the other patients were admitted to MarburgUniversity Clinics.

Of the 31 patients seven patients died, but the eighth patient survived. Prof. Siefarth remembered the Serum method of Emil von Behring, Dr Thimm says. He asked the patient who had survived to allow him to take some blood and give it after centrifugation with his own blood cells back to him. The patient agreed and so Prof Siefarth produced a fresh serum of the patient who obviously was able to produce antibodies against the suspected very aggressive microorganism.

Prof Siefarth then treated the following 23 patients with the serum of the eighth patient plus the full intensive care in the isolation unit and expensive symptomatic treatment and no more patients died. Naturally all further importations of the Green Vervet Monkeys from Uganda to Germany were stopped and Tom Mann went back to South Africa where his wife came from.

The reservoirs of the virus:

Dr Thimm recalls that Dr Siefarth wrote to him in Uganda.

"He asked me whether I could find out which other animals except the obviously healthy looking green vervet monkeys can be found as a natural reservoir or would also carry at least antibodies against this suspected virus," Dr Thimms says.

For virus isolation,very sophisticated treble isolated research labswould have been needed, which were not available in Uganda at that time."But although I was the an experienced veterinary doctor, I also did not have the means and the time left in the AHRC to go into this very difficult research for Siefarth" Dr.Thimm says.

He said he had examined the monkeys while wearing protective gear. That might have been the reason to why he survived after the investigation of the animals, not acquiring the virus during that time.

He wrote back to Prof. Siefarth saying that "I am already sitting on my packed suit case to take up my new job in Munich University. Please, send me your Assistant and I will give him all support to get the laboratory animals he needs from the Centre and to collect wild animals with the support of the Veterinary Services and Game Departments, as you need."But he also had no means for this very important research. Even members from the Centres for Disease Control, Atlanta, Georgia, USA who came, could not find the natural reservoir and carrier after isolating Marburg Disease Virus.

In Munich, Thimm was to start the Institute of Comparative Tropical Medicine with Medical and Veterinary Colleagues under Professor Dr. Albert Herrlich to do zoonosis research.

From monkeys to bats:

In their research Thimm said they found out that the monkeys were not the primary sources of the virus or else they might have died from the virus before (meaning the epidemic started a long time ago) but by the time he got in contact with them they had passed that stage. And now they were at the carrier stage where the virus usually does not kill its host anymore.

At that stage the aggressor (virus) looks to infect also human beings but could not cause a reaction of the body with symptoms (called disease)because the host has got a natural barrier or "species barrier", which protects it against new virus diseases. For example, a dog can never get measles.

With all those findings, Thimm said they did not know which animal reserved the virus. They were yet again cut between whether it was the African green monkeys or another unknown species of the monkey family.

Thimm, said that scientists had progressed in there research on Marburg, but it took them 40 years to discover the right animal which reserved the virus.

Accidentally, Thimm said, in 2008 it was reported that a 41-year old Dutch woman came to Uganda and visited the python cave in Maramagambo forest. She inquired from the locals whether it was deep and they told her it was a haunted cave with ghosts and therefore not a good place to enter.

Thimm said, she laughed and told them they were joking. She went into the cave and may have touched the wall or some stones inside the cave smeared full of urine or feces of the fruit bats, hanging down from the ceiling. When she reached Netherlands she started vomiting, having high fever and developed all the known typical symptoms of Marburg Disease. She died.

Her death though fatal, solved the world's unanswered question for the past 40 years. The fruit bat was studied and it was found that it is the primary source of the virus.

After the death of the Dutch patient and the discovery that another American woman who had visited Python Cave had acquired the virus within the same year, further testing confirmed that the fruit bat is indeed the primary reservoir for the Marburg virus.

How did the monkeys get infected?

Dr. Thimm said in veterinary medicine, there is a term called "street canopy" a term used referring to 'monkey roads'. Apparently, in the forests monkeys have designated "streets" they use when they are going to feed.

And since the fruit bats also fly, they go up on those trees and feed there. So it is presumed the monkeys got in contact with the saliva or the urine of the fruit bats or they got infected through the food chain when both animal families feed on the same food whereby vulnerable animals run a way, even if they are feeding, when the animals on top of the food chain appear.

In this case the fruit bats and the monkeys fed on the same fruit when the fruit bats flew away and left unfinished bananas behind.

Solutions to the Marburg outbreak:

Dr. Thimm says 'environmental hygiene' should be considered in relation with how these viruses keep evolving.

"We are part of nature and every time these parasitic species want to multiply they will look for a new host and human beings to infect," he says.

He says the fruit bats are part of nature and they must eat and as long as people do not stop producing bananas the fruit bats will be here. Moreover it is the fruit bats which also fertilize the banana flowers. Killing them all would mean killing the big banana industry and the base of matooke eating daily food of most Ugandans.

But he warns that people living in these areas should avoid touching bananas which have been opened by fruit bats and if they should, they have to use gloves before peeling them. He says it's much better to bury the opened fruits.

"This is because the fruit bats might just lick or urinate on the plant and not eat them. So caution should be taken when handling bananas," he says.

And if they must eat these bananas, Thimm says, we should boil them thoroughly because the Marburg virus is killed with heat. He said that although there is caution, people should not stop eating bananas. "There is nothing like a risk free life" he says.

He adds that in the last 40 years the world has experienced one new disease on average per year and in each new disease there is an animal disease behind it affecting human beings like Ebola, Lassa Fever, Avian flu, Hansa virus, Marburg, HIV/AIDS which always start with severe and aggressive strains, killing their first infected hosts and are usually buried with them. This makes isolation and research on the virus difficult when the bodies are already decomposed.

Dr Thimm says doctors could also try using the serum of the surviving patients after pasteurization to treat those who are still sick just like Prof. Siefarth did. Butwould it help without having a fully equipped intensive care and isolation unit?

He advises Ugandans not to behave like the British researchers' before independence who wanted to kill all African gazelles in Uganda to control the Tsetse flies because the latter were the primary reservoirs of sleeping sickness as the tsetse fly feeds on them as their natural host. But after 60 years of research on the lifecycle of tsetse flies, they found a better solution for controlling the disease without killing the possible carrier species among the wildlife.

He also says developing preventive measures, like gazetting all areas where fruit bats are being found and bananas grown would help researchers to study the Marburg Disease. He also recommends starting a Research Institute for Zoonotic Diseases, like the Centers for Disease Control in Atlanta, USA, which could also include research in the plenty of wildlife species in the beautiful Uganda. There are more than 300 Zoonoses, meaning diseases of animal origin which have spread to human beings that have already been identified.

Mainly, Dr Thimms says, the government needs to set up a surveillance team to catch any outbreaks in time.

With no vaccine against Marburg diseases as yet, which will probably never come as Marburg disease is such a rear disease, Thimm says a quick diagnosis of its existence with the help of a well-trained and equipped Virus laboratory, and an equally quick containment of its spread by absolutely dense isolation of suspected patients is by far the most effective method against Marburg disease. He says the Uganda Medical Service has very effectively proved again that it can do this.

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