Ebola, Marburg, and Hemorrhagic Fever

If AIDS is one of the slowest killers, taking a leisurely 10 years or so to kill its victims, Ebola is one of the fastest.    It first came to attention in 1976 when the "index case" (i.e. the first observed case) showed up at the Yambuki Mission Hospital and was mis-diagnosed as showing early signs of malaria.  He was given an injection of Chloroquine.  Apparently the same needle was used on this patient as on a number of other patients subsequently, and they developed symptoms as well.  The Index case, a mission worker, who had been on a road trip with six other mission workers, visiting several other towns in the region, and had bought smoked and fresh antelope and monkey meat on August 22, was admitted to the Yambuku Mission Hospital on Sept 1 after a "relapse" of his symptoms of what was thought to be malaria.  At that time he suffered hemorrhages and gastrointestinal bleeding, and finally died on September 8.

 To make a long story short by October 24, there had been 318 cases of the hitherto unknown disease and 280 deaths and 38 serologically confirmed cases which survived the infection.  The fact that the outpatient clinic was re-using needles and rinsing them out in a pan of warm water was implicated later as facilitating the spread of the epidemic.  By the beginning of October 11 of the 17 staff at the hospital had died from the disease and the hospital was closed.   This may have been the one thing that had the most to do with the ending of the epidemic, as the poorly trained nurses dispensed death continually, still sharing needles up until the closure of the hospital at Yambuku. 

Don't share needles and wear a protective suit

The agent of the disease was found to be related but antigenically distinct from Marburg Virus.  Marburg is a town in Germany where there is a research facility by the drug company Hoechst.  In 1967 workers were accidentally  exposed to the infected tissues of grivets, a type of monkey used for research purposes whose natural habitat is in Ethiopia and Sudan.  The virus that infected the workers also causes a severe hemorrhagic fever that in the 1967 outbreak killed 7 of 31 workers infected with it at the facility for a mortality of 23%. 

Both viruses are classed as part of the family Filoviridae, which are filamentous RNA viruses, the defining characteristics of which are outlined here.  They seem to have as their reservoir in nature, bats. 

In the case of Ebola one outbreak apparently was caused when the index case individual visited a cave near the Uganda / Zaire border.  Bats carry the virus and excrete it in their droppings while not themselves seriously affected by it.  The virus is apparently transmitted to animals such as apes or monkeys when bats feeding at night defecate on foliage which primates subsequently consume.

Acquired Immune Deficiency Syndrome (AIDS)

I can remember distinctly when all this started to rise to public consciousness.  It must have been around 1981.  I was in graduate school and I used to get a weekly publication with the charming title of "Morbidity and Mortality Weekly Report."   I remember reading the report of a "cluster" of cases of Kaposi's Sarcoma in San Francisco among homosexual men.  Kaposi's Sarcoma was a heretofore rare form of skin cancer, but now it had struck a whole group of persons living in the same city and with the same sexual orientation at the same time.

Clusters are always a red flag for the epidemiologists and the health care community.  And these men were seriously ill too.  It certainly looked communicable and a form of cancer.  And THAT was in itself very alarming.  It only occurred in immunosuppressed persons.  Moritz Kaposi, a Hungarian dermitologist from Vienna described it in 1872.  It was a malignant skin disease, but not really a sarcoma (a tumor of muscle tissue)  but serious enough.  Subsequently it has been found to have been caused (directly at least) by human herpesvirus 8.  Originally it was a disease found in elderly men of Mediterranean or Eastern European extraction, or in young African children under the age of 10.  

And it wasn't just Kaposi's sarcoma.  Other public health officials in other cities began noticing that in particular homosexual men were coming into clinics with all sorts of infections of a type that doctors only saw in cases of severe immunosupression..  It gradually dawned on people that this was all over the map.  In San Francisco, in Los Angeles, New York, Miami, Chicago, Montreal, London, Paris, Rome.  And in the beginning it seemed mostly a gay problem, but then other persons were seen with the immune deficiency:  hemophiliacs, for instance.  These were mostly children who received regularly a lot of blood products since their own bodies did not produce all the components for clotting their own blood.  This lack of clotting factors meant that a bruise or a cut could lead to death.  Now they were dying of something else entirely.   And then there were the needle-sharing intravenous drug users, junkies, persons found in all urban areas who used various injectable drugs.  Never the most sanitary of persons and with sterile needles in short supply, they shared.

There were of course many people who couldn't have cared less about what gay men did or viewed it as divine retribution for a sinful way of life,  Nor was there much concern for junkies who already seemed to be speeding on their way to the grave on greased skids anyway.   The victims were mostly denizens of a hidden urban world.  Didn't they already know that the wages of sin is death?   But then other people, like myself don't believe that what happens to people is necessarily any sort of judgment, or any such divinely ordained plan, and the rest of this article is discussing the facts without any sort of judgment at all on anyone or their tendencies. 

Gradually, however, it became evident that anyone could have AIDS, be they men, women, or children.  Many of them were drug users, and many of them were sex workers.   These were the denizens  of a hidden urban world of human beings most people would prefer not to see or think about.   But it was not exclusively a gay disease, a disease of males, or a disease of adults.  Even newborns could get the disease from their infected mothers, and when they did they seldom lived for more than a few years.

The most sensible advice to those at risk was to use a condom, and if you must share needles, clean them out with bleach (which killed just about anything) before re-using them.  As for hemophiliacs and other people unlucky enough to have received HIV contaminated blood in transfusions,  some way had to be found to make the blood supply safe, and to find a cure for those who had the infection already.

.  I knew people who knew people who had received tainted blood after some elective surgery and were thereby under a slow sentence of death. This was because blood banks in cities often bought the blood of people of dubious health in exchange for quick cash.  Maybe the blood would be tested for the presence of hepatitis B or C, which was horrible enough, but here was a problem even worse.

As investigators started to trace the history of the disease back through the maze of sexual partners in the gay community and among intravenous drug users it gradually became clear that the persons with symptoms were in the late stages of a disease that had been progressing for years and that for every person with full blown
AIDS there were many who were walking around and unaware that they were also infected, and that what they were infected with would inevitably kill them in a few years.  The immune system which is supposed to protect the individual was itself the target of the virus and proved in almost all cases, unable to resist the inexorable progression to total immunodeficiency.  The course of the untreated disease is about 10 years, with symptoms only appearing in the final  3 years.  In other words the people with full blown AIDS were only the tip of the iceberg.

Montagnier

 Meanwhile scientists in France and America were in pursuit of an answer to what was causing the disease. It was suspected that the virus was some kind of retrovirus and efforts were focused on recovering and culturing the virus (almost never an easy task) and then reproducing the disease as might be possible in non human primates.  Although at first there was a dispute as to who first isolated what became known as the Human Immunodeficiency virus (the French called it LAV, the Americans HTLV-III) it is now believed that Luc Montagnier's group in the Pasteur Institute was the first to isolate the virus.  Robert Gallo's group at the National Institutes of Health in the US claimed also to have isolated the virus.  The fact that Gallo's isolate matched the genetic make-up of the Montagnier isolate made it clear that some kind of inadvertent sharing of the Montagnier virus had occurred but this was not resolved until years later and after an official inquiry.

Gallo

Subsequently a means of detecting antibodies to HIV was found and when the beginning of widespread blood testing  occurred, it showed the truemagnitude of the problem.

What was discovered was that the virus is a retrovirus, an RNA strand which copies itself and inserts itself into the genome of the infected cells followed by replication of copies of the RNA virus and the production of particles which bud off and go on to infect other cells.  The cells that the virus infected happened to be an important part of the immune system itself, a subset of T cells which bear the CD4

receptor.  And not only CD4 positive T cells but the CD4 positive cells present in the intestinal mucosa, where CD4 positive T cells also express CCR5, which along with the CD4 receptor serves as the access point for the invasion by the HIV virus of the cell.  Then an immune response occurs which greatly reduces the infection and the initial flu like symptoms die down.  Unfortunately while the infection is checked for a time, it is not eliminated, and the virus slowly but steadily reduces the CD4/CCR5 cells until at some point a fatal immunodeficiency finally occurs.   During the period of latency the infected person feels well, something  which can last for years, when the HIV positive person is seemingly healthy and unwittingly  passes the infection along to anyone and everyone he or she may have sex with.  It is axiomatic in microbiology that the successful disease agent doesn't kill its host too quickly, but gives it time to pass the disease on to other hosts. 

So where did the HIV virus come from, and how did this happen?  Apparently from Africa where it had been present in the primate population there for thousands of years.  There are actually two different forms of HIV, HIV-1 and HIV-2.  While HIV-1 is thought to have originated in Cameroon among Chimpanzees in central Africa, HIV-2 originated in the sooty mangabey in coastal West Africa.  Both forms of HIV were derived from SIV (Simian immunodeficiency Virus) which is endemic in non human primates in Africa. It is now thought that SIV commonly was transferred to humans engaged in the hunting and preparation of "bush meat" from chimpanzees and other non human primates and that mutation in human hosts led to the evolution of HIV.

This rapid mutation rate, typical of RNA viruses, allows the tracing of various strains of virus to their likely origins. In a November 2007 article appearing in the   Proceedings of the National Academy of Science, a detailed genetic analysis of various forms of the HIV-1 virus suggested that it first came to the US in 1966.  The earliest documented case of AIDS in the US was that of a teenager from St. Louis, Missouri, named Robert Rayford.  He is thought to have been a male prostitute and since he died in 1969 at the age of 16, it is thought he must have contracted the disease as early as 1966.   Years after he died, his tissue samples were shown to contain antibodies to HIV antigens using the Western blot method.

In this age when roads have been built and people can traverse whole hemispheres in a matter of hours, the potential for spread of certain very nasty diseases is far greater than it used to be, when humans were more isolated and lived out their whole lives not far from where they were born.

Combining "high risk" sexual behavior with travel to far away places is a potent formula for disaster.  In much the same way as the sailors who sailed with Columbus brought syphilis back to Europe after 1492, HIV went from being a local virus to one that suddenly found itself in Haiti and then in the major cities of the US.  There it did not create a stir for almost ten years, when finally those who had been infected with the disease began to die in numbers that caused public health officials to notice.

 It is thought in fact that HIV may have been present in Africa as early as 1910.  The PNAS article cited above postulated in a very convincing way through detailed genetic analysis of different strains of HIV that the spread of AIDS was a consequence of of sex tourism to Haiti brought HIV to the US, after having been brought to Haiti from Africa in the early 1960s.  The virus was also found in Trinidad and Tobago and was spreading through the US in the gay community in the early 1970s.  In his book And the Band Played On, the AIDS activist Randy Shilts suggested that a gay Canadian air steward named Gaëtan Dugas was the source of the AIDS epidemic in America, having brought the disease from Africa and spread it to the gay communities of a number of American cities.  He was able to do this because of his prodigious sexual appetite and his mobility as an airline employee.  This is plausible enough, but it fails to explain the entirety of the phenomena of the early spread of the AIDS pandemic. 

Patient Zero and his sexual contacts

  This tracking of the HIV virus is possible because of its relatively high mutation rate and the sequencing and comparison of different HIV genomes.


By delving into the freezers of pathology labs in Africa, the US and Europe, preserved samples of tissue from

unexplained deaths from long ago have yielded evidence that the AIDS virus was around as early as the 1950s with the unexplained death of David Carr from Manchester, UK who died in 1959 and another 1959 sample of blood taken in Kinshasa in the Republic of the Congo in 1959 as well.  In 1973 2/3 of Ugandan children whose blood was sampled for a Burkitt's Lymphoma study, were retrospectively found to have antibodies to HIV. 

Whatever can be said for the devastation of the AIDS epidemic in the US and Europe, the picture in Africa is far worse.  With only about 15% of the population of the world, the continent of Africa contains about 70% of all living AIDS patients and accounts for about 70% of all AIDS deaths as of 2011.

Over 15% of the population in South Africa and Botswana is infected with HIV, which means more than 3 out of every 20 persons.  The countries of Southeast Africa from Rhodesia to Kenya have a prevalence of 5-15%.  And Subtype C of HIV-1, rare in the developed world is predominant in Africa and has a more rapid progression to death than other subtypes, where the progression takes about 10 years. 


It is fortunate that treatments for HIV infection have been found, a combination of antiviral drugs.  Unfortunately they are expensive, very dependent on compliance, and may cause serious side effects.  Also, while the life of the infected person may be extended many years, up to 40 perhaps, as yet there isn't a cure, a way of eliminating infection completely from the body.

And the timing of the treatment course is important as well, since those who present with AIDS cannot be easily restored to health and have a life expectancy at that point in months rather than years.

The Black Death

This disease has come down through  history with a number of names, the Black Death, the Black Plague, the Bubonic Plague.  It has probably swept through the populated world at least three times, once in the 542-543 AD (The plague of Justinian) , in 1347-1353, and in 1855, spreading from Yunnan province in China and finding its way to India and even the US.    In the 14th century it killed about 30 to 60% of the population of Europe, not to mention parts of Asia, Africa, and the Middle East.  The 14th century pandemics were followed by periodic and more limited waves of plague 

 At the time there was very little understanding of what caused the disease, other than it was highly contagious, very likely to result in

death, and  its symptoms invariably included gangrene in the fingers and toes, where the skin turned black.  Another symptom was swelling in the groin, the armpits, and the neck known as buboes, which gave the disease its modern name, the bubonic plague. 

The result was the depopulation of certain parts of Europe, political and religious upheavals,  Geoffrey Chaucer's "The Canterbury Tales" and Boccacio's "The Decameron" were literary expressions of the ferment that resulted from all of world society being turned as it were, upside down.

Geoffrey Chaucer

The disease agent is Yersinia pestis, a gram negative coccobacillus and facultative anerobic bacterium.  What that means is that it has a round to rod like shape, it does not stain purple using the Gram stain  ( a basic method of classifying bacteria), and as a facultative anaerobe, it can take oxygen or leave it, depending on the circumstances.    Bacteria can be found just about anywhere and most of them in

Fluorescent Stained Y. pestis

most contexts are harmless, but not Yersinia pestis.  It started out as a disease of rodents and fleas and remains such a disease from the sewers of China to the prairie dog towns in the American great plains.   Rats and all small mammals are infested with fleas, the fleas are infected with Yersinia pestis, which grows in its gut, and when the flea regurgitates its bacterial load while feeding on the blood of the rat, thus giving the rat the plague.  The fleas

Flea engorged with Y. pestis

probably don't much like the infection either, but their health is of least concern.   The rats or other rodents   suffer some ill effects from the infection as well, but from long exposure to the disease, natural selection has seen to it that they live long enough to spread the disease. Occasionally since rats live in close proximity with humans, this led to humans being infected as well.

Diseases, when they jump species tend to be especially severe in the species that is new to the organism.  Thus it was that what may have made rats merely sick, made most humans die.  This combined with the Silk road, which allowed commerce to travel from the China to Europe, and with water routes, where rats lived and prospered in the holds of ships, going ashore along the ropes used to lash the boat to the pier, sharing their infected fleas with rats living in the port, and both sharing their disease with the sailors and port personnel who were bitten by the infected fleas.  In central Asia the flea-rodent reservoir was a variety of ground rodents as well as marmots.

Marmot

 

The plague is thought to have originated in the steppes of Central Asia along the silk road.  Nestorian graves in Kyrgyzstan in 1338 mention plague and this is thought to have been the time and the locus of the initial outbreak. This means that the plague spread to the far reaches of Europe within less than 15 years.   It spread west and arrived in the Crimea either by the silk road or by ship by 1346.  From there it spread rapidly to ports and islands in the Mediterranean in 1347, throughout southern Europe by 1348,  to England and Germany by 1349, to Scandinavia by 1350 and throughout Scandinavia and Russia by 1353. 

It is said to have reduced the population of the planet by around 1/5 by 1400.  It returned periodically from time to time after that.  It struck London in 1603 and again in 1665-6, Vienna in 1669,  Italy in 1629-31, Seville in 1647-52,  Marseille in 1720-22, Eastern Europe in 1738, and Russia in 1770-72.

When the first wave came through it reduced the population of Europe by about 50%, especially in the urban areas where people lived close together.  In the southern areas of France, in Italy and Spain it was estimated to be as much as 70-80% mortality. 

A real scientific understanding of the disease and its epidemiology had to wait for the late 1800s. 

At that time during an outbreak in China, Alexander Yersin (for whom the pathogen is named) identified the bacterium that caused the disease, it was named Yersinia pestis.  The epidemiology was worked out by Paul-Louis Symond in 1898, establishing the way in which fleas and rodents spread the disease.  Apparently the disease can be spread through aerosols, as in Pneumonic plague, or from flea bites as in septicemic plague or bubonic plague.  Analysis of trace DNA from persons who died in the earlier centuries established the identity of Y. pestis as the cause of the great pandemic of 1338 to 1353.

Chinese immigrants and trade with China   probably brought the plague to the US with an outbreak  centering on San Francisco in 1900-1904 and another wave of plague occurring in 1906.  That was the year when most of San Francisco was destroyed by an earthquake and then a fire.  Plague then passed into the local ground squirrel population and has since become endemic among wild rodents and the mammals that prey on them. 

In recent years it has decimated prairie dogs, a ground dwelling rodent common in the Western US.  Occasionally people become infected, getting the disease from their pets. In one case a wildlife biologist working in the Grand Canyon National Park   contracted it from a mountain lion on whom he was performing a necropsy, and before anyone suspected what was going on, he was dead.   Especially in the western US it is wise to take serious precautions when handling the corpses of wild animals or game. 

Except for cases such as these, the increased awareness of how disease spread and  improved sanitation of most cities in the last century has much reduced the possibility of such pandemics from occurring in the future.