Posts Tagged ‘pandemics’

Cholera: Part 1 background and history

Sunday, February 24th, 2013

An 1882 monument to victims of cholera

Cholera is an infectious illness, found only in humans, caused by a bacteria in contaminated water, leading to severe diarrhea and dehydration and capable of killing its victims in a matter of hours if untreated. When I read about the disease for the second time in decades (the first time was after a 21st-century epidemic in Haiti), I was amazed at how quickly a victim can lose 10% or more of their body weight in severe cases; e.g., eight quarts between my normal bedtime and when I usually wake up. Many people who ingest the bacteria don't develop any symptoms, but if they do and lack modern re-hydration therapy, their chance of dying is 40-60%.

In all likelihood it is an ancient disease with writings from the lifespan of Buddha  (563-583 BCE) and from the time of Hippocrates (460-377 BCE) revealing diseases that presumably were  cholera. It has, over the last several hundred years, been a major killer of mankind, causing millions of deaths in the 19th century.   Those numbers place it among the deadliest of infectious illnesses, in the company of smallpox, the Spanish flu, bubonic plague, AIDS and malaria.

A CBC News article online with the title "Cholera's Seven Pandemics," starts with a major outbreak in India near the Ganges River delta. Between 1817 and 1823 there were 10,000 deaths among the British soldiers stationed in that country, estimates of hundreds of thousands of fatal cases among native Indians and 100,000 dying in Java in the year 1820. The second pandemic began in 1829, again in India, and spread to Russia, Finland, Poland, England, Ireland, Canada, the U.S. and Latin America, before another outbreak in England and Wales that killed 52,000 over two years. The sixth pandemic killed more than 800,000 people in India alone and, over the next 24 years swept over parts of Europe, Russia, northern Africa and the Middle East.

The National Library of Medicine's website entry on cholera associates it with crowding, poor sanitation, famine and war. India has remained a source as the disease is endemic (ever present) there. People get cholera by eating or drinking either contaminated food or water; the medical term is the fecal-oral route.

In the summer of 1854 London was the epicenter of a deadly outbreak. Dr. John Snow, a famous British physician born March 15th, 1813, had been noted as a pioneer in anesthesiology, using chloroform to assist in Queen Victoria's delivery of her eighth child in 1853.

Then, as documented in the book, The Ghost Map by Steven Johnson, Snow turned his investigative talents and keen mind to cholera, becoming in the process the modern father of epidemiology.

London's population had grown immensely and its sewage system was antiquated. In addition to basements filled with excrement, cesspools and drainage into water sources were rampant. A major concept of disease causation was the miasma theory. The term means "bad air" and the assumption was illness was caused by the presence in the air of a miasma, a ill-smelling vapour containing suspended particles of decaying matter .

Snow, on the other hand, felt cholera was caused by something ingested, most likely by drinking water contaminated by waste products.

In a painstaking and extremely clever investigation, Snow had, in a prior cholera outbreak in 1849 which was responsible for a dozen deaths in flats in a slum area, shown that two separate  sets of milieu had markedly differing death rates. All environmental parameters were essentially identical in the two groups with one exception; where they obtained their water. The group who suffered a much higher rate of illness got theirs from a company whose river source was in the same area where many sewers emptied.

Vibrio cholerae, the cholera bacteria

Five years later a much larger cholera epidemic provided an opportunity to more closely examine the water sources of the victims. One particular pump, seemingly providing clear water, proved to be the culprit. The Broad Street pump's output was examined by a Snow's colleague, a skilled microscopist Dr. Arthur Hassall, and found to contain what Hassall believed to be decomposed organic matter with oval-shaped tiny life-forms felt to be feeding on that organic substance. Snow was not aware then of the 1854 work of an Italian scientist, Filippo Pacini, who had examined the intestines of patients dying from cholera in Florence and found a comma-shaped bacillus he termed a Vibrio.

The proponents of the miasma theory did not yield easily, but Snow's map of the location of deaths from cholera eventually let his hypothesis of a water-borne illness prevail.  Then an assistant curate (church figure in charge of a parish) named Henry Whitehead who had read Snow's papers on the epidemic eventually found the index (first) case, a baby Lewis. As a result, the Broad Street pump was excavated and a direct connection to a cesspool was found.

The juxtaposition of Snow's scientific data and Whitehead's work as a beloved neighborhood figure led to the local Vestry Committee's report endorsing the water-as-culprit theory.

The city subsequently launched a major project to carry waste and surface water away from Central London.

 

 

 

 

Five years later, he

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Coughs, colds and flu Part 2: what's new with flu?

Thursday, January 17th, 2013

Like we always do, we got our flu shots early, this year on the day after they first became available. Several friends said they were going to wait a few months; I'm always concerned that the supply of vaccine will be gone by then and as former Air Force medical staff, we got in the habit of being told, "It's time for your flu shot." Our timing was excellent; flu struck earlier than usual (it typically peaks in February). And the New York State Department of Health agreed that the best time to get a flu shot is as soon as the vaccine is available.

This is a bad flu season with not only an early peak in case numbers, but also an unusual virus. I looked at the flu primer, updated for the 2012-2013 season, by arstechnica, a technology news and information website. The influenza virus has an outer layer of proteins around its genetic material core; the specific proteins of the coating determine what kind of cells the flu bug can attach to and therefore infect  (they also act as chemicals that our immune system can react to), while the inside core lets the virus take over the cell and make new viral particles.

flu virus with Hs and Ns sticking out; I think of them as arms and legs

The most important proteins in the outside coating are called hemagglutinin (H) and neuraminidase (N); there are a variety of each with the CDC saying there are 16 different Hs and 9 Ns. Three variants, H1N1, H1N3 and H3N2, are currently infecting humans while the highly pathogenic H5N1 avian flu was of major concern in recent years. As of January 5th, 2013, the influenza A H3N2 virus was the predominant strain causing flu in the United States.

There are three types of influenza viruses, logically enough labeled types A, B and C. Type A can affect both humans and some animals and is responsible for the largest and most widespread  outbreaks termed pandemics. Type B only occurs in people and usually is responsible for less severe reactions; it is not classified by subtypes and isn't responsible for pandemics. Type C, also only a human strain, doesn't cause epidemics, much less pandemics and doesn't lead to severe illness. The yearly vaccine protects against two type A strains (H1N1 and H3N2) and one type B virus with specific viruses chosen based on scientific estimations of what the coming year's flu will most likely be. The CDC webpage titled "Key Facts about Seasonal Flu Vaccine" mentions three different flu shot varieties and one nasal vaccine; the shots are all made from inactivated viruses (one is a high-dose form designed for those of us 65 and older). The nasal spray is made from live attenuated (weakened) viruses and can be given to anyone age 2 to 49 who is not pregnant and is otherwise healthy.

Now civilian hospitals in a number of areas have fired staff members who refused to get vaccinated for influenza. Some of those former hospital employees are threatening to sue, but my own viewpoint is the hospitals have done the right thing. The last thing I think they need is their own docs, nurses, techs and other staff infecting patients who are already ill with something that may make them more likely to have flu complications.

What about pregnant women who work for the hospital? Should they get flu shots or does that place their fetuses at risk? I wasn't sure until I saw the 1-16-2013 edition of the New England Journal of  Medicine. A Norwegian study performed during the 2009 flu pandemic had convincing figures: there were 117,347 eligible pregnancies and 54% of the women were vaccinated in their second or third trimester with substantial reduction in moms getting the flu.

Pregnant women in this study who did have influenza had an increased risk of fetal death. Vaccination did not increase fetal mortality (and may actually have reduced it).

epidemics are many more cases than usual; pandemics have widespread cases

The real problem with bad cases of flu is bacterial coinfection, often with "bugs" that colonize our nasopharynx area: staph aureus, strep pneumoniae and strep pyogenes. This highly significant flu complication was present in almost everyone who died in the great flu pandemic in 1918 and, even today, with our panoply of antibiotics, frequently occurs in influenza victims who require ICU care. A third of those needing such intensive care in the 2009 H1N1 pandemic had such a combined illness.

The CDC has a superb webpage, "What you should know for the 2012-2013 Influenza Season," and I strongly recommend using that as a source.

Here's hoping you get a yearly vaccination and don't ever get the flu.

 

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The 1918 flu: Part 3: Gene sequencing and reconstructing the virus

Tuesday, May 15th, 2012

here's a starting point

So how do you re-create a virus? Or at least understand how it did what it did?

In the previous post I brought us up to 1995 when Jeffery K Taubenberger, who had received a combined MD/PhD degree at the Medical College of Virginia in 1986-87, and then went to the National Cancer Institute for pathology training, got interested in the 1918-1919 influenza virus.  He used the technique known as polymerase chain reaction (PCR ) which allows a researcher to make many copies of a short segment of DNA inexpensively (If you click on the link you can experience PCR yourself). It was invented by a scientist named Kary Mullis who won a Nobel Prize in 1993 for his novel approach to genetic information.

Taubenberger and his associates went to the National Tissue Repository (NTP) and found 70 of the 100 autopsy files from the pandemic had tissue samples; 13 of these seemed candidates for recovering RNA and two actually yielded suitable RNA fragments. Data from the first case showed the virus was an H1N1 subtype and the second NTP tissue plus that obtained by Hultin in Alaska enabled the next nine years of the project, sequencing the genome of the virus.

The process is described in the Human Genome Project Information (HGP) packet online, but in brief  the genetic material is broken into small chunks, each of which is used as a template, a model to be copied. Those models allow the research team to make duplicate fragments that have slight differences in which chemical bases (with abbreviations A, T, C, and G for DNA and U substituting for T in RNA) are present. Other steps, many of which are now automated, allow the re-creation of the sequence, the pattern, of the bases. In 2006 the HGP group finished enormous task of mapping the DNA sequence for all 24 human chromosomes.

In the meantime Taubenberger and his colleagues had moved into the field of reverse genetics technology, trying to find out what physical characteristics (the scientific term is phenotype) are due to a particular gene, by slightly altering the gene's structure. Their 2007 paper, available in PubMed Central, a free digital database of full-text scientific literature in biomedical and life sciences, describes their efforts to sequence the entire genome (all of the biological information needed to build and maintain a living example of that organism) of the 1918-1919 influenza virus.

Then they could perform actual experiments with viruses that had at least one of the 1918 flu virus genes. They were very careful with this work; their research was performed two labs that had been through the laborious certification process as BioSafety Level 3 or higher. The new viruses that had all eight genes from the 1918 flu were considerably more damaging, in animals at least, than those that had less than the full complement of genes.

Their conclusions, at this point, were fascinating: the 1918 virus was likely brand new, at least to mankind and came from an avian source, but which bird was involved is unknown. They haven't been able to determine yet exactly why the human infection was so deadly.

It could be a deadlier version of this one

They think we're at a mid-point in understanding the worst flu pandemic and we clearly need to learn more about it.

Why? Because other influenza virus mutations will eventually be coming our way.

 

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The 1918 flu virus and its descendants: Part 2 Rediscovering the culprit

Sunday, May 13th, 2012

many other major pandemics were associated with rodents, but not the 1918 flu

I re-read my last post a day after writing it and amended the first line, since I found it misleading. It was the worst flu pandemic ever, but I knew that smallpox, the Black Plague, AIDS, malaria and perhaps even typhus each have caused nearly as many or even more deaths over a period of years. I eventually found a rather strange, non-medical website with the "7 Worst Killer Plagues in history," and confirmed my belief that no other bacteria or virus had wreaked as much havoc in brief span of time as the 1918-1919 H1N1 influenza virus.

I wanted to find out what happened to that highly pathogenic organism and, after searching the web, realized the PBS article on the "Spanish flu" was a good place to start. It mentions that the influenza virus was not identified until 1933 and that the actual genetic identity of the particular strain involved in that pandemic (as opposed to the basic type...H1N1) was not identified for many years. The influenza virus responsible for the 1918-1919 pandemic has had many descendants, none as deadly as their ancestor.

In 1950, Johan V Hultin, a graduate student starting his doctoral studies in microbiology, got a clue from a visiting professor who suggested hunting for the virus in bodies buried 32 years prior in the permafrost of the Arctic. Hultin and his faculty advisor traveled to Alaska where flu among the Inuits had been especially deadly with 50 to 100% death rates in five villages.

early days in the Far North

Gold miners, under contract with the Territorial government, had served as grave diggers in 1918-1919 and tissue samples were recovered from four bodies exhumed in 1951. Pathology slides fit with viral lung damage and, in some cases, secondary bacterial pneumonia. But tissue cultures from the samples did not cause disease in ferrets and no influenza virus was recovered.

It wasn't until 1995 that science had advanced enough to for researchers to start the work necessary to identify the virus's unique features. Jeffrey Taubenberger, a molecular pathologist then working at the Armed Forces Institute of Pathology (AFIP), began a ten-plus-year-long project starting with autopsy tissues from the time of the pandemic that had been preserved in the National Tissue Repository. His project was stimulated by a paper published in the journal Science in February, 1995, in which preserved tissue samples from the famous British scientist John Dalton (often called the father of modern atomic theory) were examined. Dalton was color-blind and had donated his eyes at his death in 1844 to determine the cause of the defect; his DNA was studied 150 years later and the resultant publication gave Taubenberger the impetus to do the same with the flu virus.

Hultin read the first paper from Taubenberger's group, wrote to him and eventually went back to Alaska to exhume more flu victims. One was an obese woman whose lungs had the findings of acute viral infection. Samples of these permafrost-preserved tissue had RNA incredibly similar to those obtained from the AFIP National Tissue repository.

And so began an amazing chapter in the history of virology.

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The 1918 flu and its descendants: part 1

Friday, May 11th, 2012

In some years this sign should be in red

The worst flu pandemic of all time began near the end of World War I, in the fall of 1918. It killed, in the next year, somewhere between 20 and 50 million people across the globe.  The comparison to WW I deaths, eight and a half million from all countries involved, is striking.

There had been major influenza pandemics before and since, some severe and some relatively mild. The term itself conventionally refers to a worldwide outbreak of an infectious disease with some adults in every continent (except Antarctica) involved, but doesn't imply how lethal the illness is.  For example the H1N1 "swine flu" pandemic in 2009-2010 involved 74 countries, but the death rate was relatively low.

Stanford University has a superb description of the so-called Spanish flu online. Usually flu kills the very young and the very old more than young adults; this time was different with far more deaths between the ages of 20 and 40 (some say 20-50 and others 15 to 34) than in the typical flu season. The influenza-related death rate, normally about 0.1%, has been estimated at 2.5 to 3% and may have been even higher. A fifth to a third of everyone alive at the time caught the virus, so half a billion victims may have been inflicted.

For Americans, including soldiers, the end of the war was near, but over 40,000 servicemen and nearly two-thirds of a million back home would die of this modern plague.

The precise origin of the disease is unclear; swine were affected in a nearly simultaneous fashion, but have not been blamed for the human ailment. The war itself and its resultant transportation of large numbers of troops, could have facilitated its spread globally. A first wave of the infection struck American army encampments in the United States, but was comparatively mild, at least when contrasted to the second and third outbreaks later in 1918 and then in 1919.

He was at risk as well

Public health measures were widely instituted, but the actual effectiveness of quarantine, gauze face masks, limited school closures and banning of public events is unknown.

In the midst of what for many was a typical flu infection, some developed a highly virulent form of the disease, with a strikingly abrupt onset, fever, exhaustion and rapid progression to pulmonary complications and death.

Many cases developed secondary bacterial infections and one species of bacteria was initially blamed for the disease. Then two French scientists reported a filter-passing virus in the British Medical Journal in November 1918. They used filtration to remove bacteria from the sputum coughed up by a flu patient and then injected the remaining fluid into the the eyes and noses of two monkeys. After their primate subjects were noted to have fevers, a human volunteer was given a subcutaneous injection of the same filtrate. He was the only person in their laboratory to develop the flu.

The extraordinary mortality rate of the 1918 influenza is shown on a graph plotting deaths in America from a variety of common infectious diseases over the years from 1900 to 1970. Another way to gauge the impact of the pandemic is to note that average life expectancy in the United States fell by ten years for that period.

And yet the incidence of influenza ebbed and since 1920 we've returned to the normal cycle of seasonal flu, intermittent epidemics and occasional pandemics, none as severe and deadly as the Great Flu of 1918-1919.

 

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Dangerous research on influenza H5N1, the "bird flu"

Tuesday, March 13th, 2012

This "chicken" is safe to handle

I just looked at the World Health Organization's (WHO) most recent statistics on human cases of avian influenza H5N1, the dreaded bird flu. These cover the period from 2003 through March 10, 2012 and report 596 total cases and 350 deaths. The counties with the great numbers of cases are Indonesia, Egypt and Vietnam and I didn't see any reports of bird flu infections in the Western Hemisphere...yet.

That's a relatively tiny number of cases, but an incredibly high percentage of deaths, nearly 60% of those infected. But influenza epidemics and pandemics have been a common occurrence in the last century. So what's the difference between our seasonal flu, the pandemics and this new flu?

The Food and Agriculture Organization of WHO has published the first three chapters (of nine) of an online primer on avian influenza. It seemed a good place for me to start.

The first issue is how easily a new flu virus passes from animals  to humans (the usual hosts are birds, typically ducks and, secondarily, chickens, especially if flocks are raised in proximity to each other and the ducks are "free range") and then from one person to another. The second is how deadly the particular influenza virus is.

Up until now those infected with the relatively new H5N1 subtype, sometimes called H5N1 HPAI, have had direct or at least indirect contact with infected birds. The HPAI is the acronym for "Highly Pathogenic Avian Influenza," but in this case highly pathogenic, which translates into very likely to cause disease, mostly refers to birds. Unlike seasonal flu, there's been (thus far) absolutely no documented human-to-human spread of the virus.

The 1918 Spanish flu infected 1/3 of everyone alive and killed at least 20 million. My math says that's roughly 4%, but 3% is the usual quoted figure. Seasonal flu kills less than 0.1% of those infected. So this flu, if it does reach a human, is terrible.

These experiment may prove deadly

Recently there has been an enormous flap about the work done in two laboratories. I had heard about the issue, but hadn't read the details until my monthly copy of On Wisconsin arrived and I realized one of the labs was in Madison. CNN has an online review of the problem. The researchers wondered why this deadly flu variety hasn't spread from person to person, so they created a mutated form that could be easily transmitted from one mammal to another using ferrets as their test animal.

Then the excrement collided with the rotating blades. Detailed papers were about to be published in prominent, widely read journals, Nature and Science. The National Science Advisory Board for Biosecurity temporarily stopped the process, saying the papers should be published without methods or details to stop terrorists from making their own highly lethal and easily spread virus strains.

Think about it; if this virus subtype gets released it could potentially infect a third or perhaps all of all of us now alive and kill 60% of those whom it strikes. We have a world population of roughly 7 billion now, so that's somewhere between 1.4 and 4.2 billion deaths.

Yet many in the scientist community seems to think all the details of the research should be given to those responsible groups that need help with H5N1 HPAI.

I'm worried.

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The "sex life" of a virus

Saturday, March 10th, 2012

The double helix

Most of us who are adults (and many who are not) have personal knowledge of human sexual reproduction, the process by which a man and a woman each contribute genetic material that contains DNA (deoxyribonucleic acid), the chemical basis of new life. DNA is an incredibly long twisted molecule. Its structure is a double helix with two strands composed of a sugar-phosphate backbone linked by four specific chemicals: adenine (A), thymine (T), cytosine (C) and guanine (G). These are called bases and match up in specific pairs, A always with T and G with C.

DNA has an amazing ability to replicate itself; the strands separate and each becomes the pattern for a duplicate to be constructed. Occasional mistakes are made, but we have a cleanup chemical, DNA polymerase, a kind of automatic spellchecker, that makes corrections.

Our human DNA has about 3 billion pairs of these bases; yours and mine and Cousin Flo's will be 99% identical. The remaining 1% is what makes the difference between an Einstein, a sports hero, a jazz musician and you and me. Our DNA is 98% the same as a chimpanzees and 85% the same as a mouse, but these comparisons clearly understate the importance a single base pair difference can make.

Viral "reproduction" is quite different. Influenza viruses don't have DNA; instead they contain RNA and have to replicate in living cells. Once they are inside one, the process results in many viral "offspring." These eventually leave to infect other cells in the organism and in doing so kill the one they replicated in. RNA (ribonucleic acid) is somewhat like DNA, but has one different base and a slightly different sugar in its "backbone." It's usually found as single strands shorter than those of DNA or, in the case of the flu virus, in seven or eight pieces. It lacks a proofreading enzyme so most of the new influenza virus copies are actually mutants.

Most of these changes, called antigenic drift, are minor. So the flu shot I get every year, which is an educated best guess as to what this years flu virus will be, offers considerable, but not total protection.

flu shots make sense

Sometimes the mutations are more significant; the process is called antigenic shift. That may occur when a host is infected with two different influenza viruses at the same time. The swine flu, for example, contained genes from pigs, humans and birds. When this happens, pandemics may occur.

Influenza is spread in several different ways: an infected person coughs or sneezes and you inhale the aerosolized virus; humans may come into direct contact with bird droppings or nasal secretions; various surfaces may become contaminated (viral particles in mucous may survive several weeks on banknotes).

Modern techniques for producing new flu vaccines rapidly may prevent millions of deaths and steps toward a "universal flu vaccine" are being researched. In the meantime logical precautions and yearly flu shots can save lives.

 

 

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Viral diseases old and new: Let's just begin with the flu

Sunday, March 4th, 2012

A cause for alarm and action

Two days ago I began a post on zoonoses, diseases that spread from animals to humans. As usual, my interest led me from one fairly-limited topic to more-generalized subjects and I eventually decide to write a multi-post discussion of viral diseases that either have caused massive, widespread epidemics (AKA pandemics) or could potentially lead to them.

The number of deaths they have resulted in is staggering. HIV/AIDS has killed over 25 million of us in the past 30 years; the Black Plague over a 330-year period killed 75 million and smallpox is estimated to have caused over 300 million deaths over the centuries.

But let's start with influenza, the virus that we read about year after year as a worldwide threat. In the fall my wife and I get flu shots; we got used to doing so when we were both on active duty as Air Force medical staff personnel. It was routine; I didn't pay a lot of attention to what this year's shot contained and only vaguely kept up with anything written about the flu itself.

Then so-called "bird flu" came along and  the world geared up for a terrible pandemic.Usually the kind of influenza virus found in birds doesn't infect humans. But one unusual strain, called H5N1 (I'll explain what that means later) killed a six-year-old boy in Thailand in 2003. Of the people who caught this virus, 60 % died.

Most of us have heard about the Spanish flu, a major pandemic that infected a third of everyone living in 1918-1919 and caused 20 to 40 million deaths worldwide. Yet only 3% of those whom the virus infected died from it.

The so-called Asian flu pandemic in 1956-1958 causes 2 million deaths; the Hong Kong flu in 1968-1969 killed 1 million and the yearly seasonal flu results in anywhere from 5 to 15% of us getting ill; 250,000 to 500,000 die as a result. But these flu strains actually only resulted in a death ratio of less than 0.1%.

As it turned out, there was very little person to person spread of the avian flu. If there had been the results could have been catastrophic.

But the pigs had nothing to worry about; we did!

One of the outcomes of the avian H5N1 outbreak was fortuitous. When the "Swine flu" pandemic occurred in 2009-2010, the public health establishment and the medical community were considerably better prepared. The CDC summary is worth reading as it documents the steps taken to contain the virus; actually this was a flu strain that was transmitted from person to person and wasn't present in US pig herds.

The virus itself had genes from four different influenza virus sources, two from pigs, one from birds and one from a human flu virus. The CDC widely distributed kits to labs enabling them to identify the new viral strain. They and the World Health Organization (WHO) kept tabs on the numbers of cases of the new disease and WHO announced a global pandemic in June, 2009 .

A vaccine was developed with unusual speed and a preliminary target group of higher-risk individuals was identified; this consisted of 159 million people in the US. Vaccine safety was tested in various groups and the vaccine itself was administered starting in early October; by late December 2009 enough had been produced to allow vaccination of anyone wishing it.

The final results were impressive; less than two-thirds of a million people caught the virus and the death rate was 0.03%

 

 

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