Archive for the ‘1918 flu pandemic’ Category

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.


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.


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.

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.


Mutating the deadly H5N1 flu virus

Saturday, May 5th, 2012

This ferret is healthy

There's been a recent controversy as to whether potentially dangerous medical information should be made available to the public. Now it's happened and I'm somewhat less concerned than I was a few weeks ago. The online version of Nature just published the work of the University of Wisconsin group on making the Highly Pathogenic Avian Influenza (HPAI) type A H5N1 virus transmissible from mammal to mammal, in this case ferrets.

This is potentially a terrible disease; it's killed 355 of the 602 humans (~59%) known to have contracted the HPAI A(H5N1) virus to date. None of those cases involved human to human spread of the flu bug involved. But that's roughly 600 times as lethal as an "ordinary" flu pandemic and more than 20 times as deadly as the 1918 flu.

So why am I less worried than I was?

When I read the article in Nature in detail (and it's tough slogging even for a physician), I realized that the virus, in the process of making it capable of airborne transmission, had also been made less virulent. None of the ferrets used as research subjects died of the disease . The new virus was also found to be preventable by a vaccine and treatable with one of the existing anti-flu medications.

The other thing I quickly understood is this is not a process that the average man (or woman) on the street or even the vast majority of scientists and/or physicians could duplicate. It involved an enormously complex set of laboratory procedures, many of which would demand long-term expertise and experience in the field. Theoretically a virology lab could be influenced by links to a terrorist group or have their own "ultra-green" agenda; neither possibility sounds at all likely to me.

The other paper, detailing the work done on HPAI A(H5N1) in Rotterdam, is yet to be published. That one has me more concerned, but I've just read a paper "Dangerous for ferrets: lethal for humans?" that carefully explores the question involved.

The authors reminded us that a previous paper had discussed the recreation of the so-called Spanish flu virus that killed 50 million worldwide in 1918. I'll write about that in detail some other time, but when that publication appeared, its authors were hailed as heroes, not as dolts.

The work of Ron Fouchier, a senior figure at the Erasmus Medical Center in Holland took the virology world by storm. He first announced his group's alteration of H5N1 at an international meeting in Malta in September, 2011. Initially his variant of the flu virus was thought to be much more deadly to ferrets than the UW bug. A May 3, 2012 paper in Time Healthland discusses the infighting among scientists that followed, but notes that Fouchier's paper should be out in the magazine Science in the near future.

Apparently Fouchier's mutated virus also turned out to be less of a ferret-killer than was initially thought.

There's the normal flu season and the other kind

But that's not the major issue here. Most of those working in the virology field feel a natural mutation of H5N1 or H1N1 or other flu strains is more to be feared than anything produced in a lab. Yet the relatively benign 1977 H1N1 flu pandemic, so-called Russian flu, may have escaped from deep freeze in a lab.

Every year has its flu season; some are much worse than others.