Archive for May, 2012

Hantavirus syndromes part 2: the Four Corners and beyond

Wednesday, May 30th, 2012

I'm normally happy to see this sign, even in the Four Corners area

It's rare to have a "coup" in medicine, but one of mine happened just over 15 years ago. In mid-May of 1993 I was making rounds with my two staff Nephrologists and their Internal Medicine residents when I heard about a disease that had just been discovered in New Mexico. I was the "old man," the Commander of the Keesler Air Force Base medical center near Biloxi, not as current in my medical reading as my junior docs, so when I ventured a guess this would turn out to be a different Hantavirus syndrome and mentioned I have saved articles on the illness in my "War File," nobody paid much attention.

Several days later the CDC announced an unknown virus, presumed to be a Hantavirus, was causing a highly lethal pulmonary syndrome. There was an immediate scramble to borrow my War File.

El Nino had brought more rain than usual to the Four Corners area in the Fall of 1992 with a resultant growth of nuts, seeds and berries. Some of the local wild animals, including the deer mice, had markedly increased their population numbers.

The initial known victim was a young, physically fit Navajo man who had abrupt onset of breathing difficulties, was taken to a hospital and died soon afterwards.

Then it was found that his fiancé had also died, only a few days prior, with nearly identical symptoms. Another victim from the same locale and then a cluster of five others, reported independently, led to a massive effort to discover the cause. More cases turned up and 80% died.

this is how your chest x-ray should look; their's were diffusely white

Each had started with nondescript symptoms...fever, chills and muscle aches, but then they swiftly developed shortness of breath, low blood pressure and abnormal chest x-rays typical of Acute Respiratory Distress Syndrome (ARDS). That could be caused by any major injury to the lungs...trauma, severe infections, chemicals.

The short list of possible causes included Hantavirus and some of the blood samples from patients showed antibodies to several subspecies of those. No known member of the group could be be grown initially, and the causative agent was titled, Sin Nombre, "Nameless."  The new disease was named Hantavirus Pulmonary Syndrome, HPS. A laboratory test was developed to allow identification of the infecting virus from autopsy tissues and the deer mouse through its urine and droppings was thought to be the vector for the spread of the disease.

By the end of 2011, 587 cases have been reported in 34 states, with New Mexico, Colorado and Arizona leading the pack. Only 3 a year are seen in western Canada. Individuals with HPS and some outbreaks have been noted in a number of South American countries as well as Panama. Stored lung tissues from people who had died years back were examined and a Utah man who had ARDS in 1959 was found to test positive for the new virus which had eventually been grown by the Army's research lab.

Other viruses with other vector species have been reported to cause HPS. Some involve features overlapping with HFRS. An associate professor at Johns Hopkins has used satellite images to develop "risk maps" for outbreaks.

With current death rates at 35- 40%, presumably due to better handling of fluids given patients as well as discovery of milder cases, HPS is still a horrific disease.

But at least there has been no known instance of person-to-person spread.

Hantavirus syndromes part 1: The rest of the world

Saturday, May 26th, 2012

dialysis for acute kidney failure

It's been a long time since I've written about Hantavirus, but I recently saw mouse droppings in our basement storage area and that brought me back to the topic. My first knowledge of this organism came from an episode of "MASH" where Hawkeye encountered a patient with a low platelet count and acute kidney failure and had to send the man to a dialysis unit in Tokyo.  I got interested in the disease that soldier contracted and, since I was on Active Duty at the time, put it in my "War File." Years later I found articles showing exposure to the virus of longshoremen in a number of US ports and then in 1993, five young, previously healthy victims who lived in the Four Corners region, where Arizona, New Mexico, Utah and Colorado meet, died of a new manifestation of this virus.

There's a thorough paper on Hantavirus available online from the Center for Food Security & Public Health at Iowa State's College of Veterinary Medicine. The disease comes in two forms: the kind I first became aware of is hemorrhagic fever with renal syndrome (HFRS) and the newer variety is hantavirus pulmonary syndrome (HPS). There are huge differences between the two types.

Let's start with HFRS. The CDC's description of this "syndrome" (the term syndrome is normally used to describe a cluster of symptoms that together are characteristic of a disease) calls it a group of clinically similar illnesses. A number of different rodents and shrews (small, insect-eating, pointy-nosed mammals) carry the virus and four of the twenty hantavirsus subtypes identified are most frequently associated with HFRS in various countries/regions.

HFRS starts abruptly with fever, chills, headache, backache and exhaustion as the most common manifestations. After a few days to a week, severe cases develop hemorrhagic (bleeding) complications and kidney involvement with some going on to shock, kidney failure and death. Intensive nursing care, dialysis and an anti-viral medication called ribavirin are used to support the patients who have this dire form of HFRS.

The fatality rate varies considerably depending on which virus subtype is involved. For one particular hantavirus, found mostly in Europe, less than 1% of those affected may die; for the form I was first familiar with, caused by the Hantaan virus, 5 to 15% of patents will die.

Worldwide, up to 200,000 people are hospitalized with HFRS every year. Most of those cases occur in Asia (with much smaller numbers in Europe); up to 8% of the population there have antibodies indicating past infection with some form of the Hantavirus.

Other animals, including cats, dogs, pigs, horses and even moose may have antibodies to the virus, but don't appear to get sick from it.

Some mice are smarter than others.

Better than treating the disease, of course, is preventing it. Making your home or other buildings mouse-proof isn't easy, but storing food in secure containers and using traps and rodent poisons may go a long ways toward avoiding the disease. The CDC website has detailed instructions on safe ways to clean up rodent droppings and urine. CDC warns you should never start by sweeping or vacuuming!

Now I need to clean up the mouse debris in our furnace room.

Heart attacks Part 2: Prevention: risk factors & our kids

Wednesday, May 23rd, 2012

Here's a risk factor you can eliminate

This post pings off the April 17, 2012 article in The Wall Street Journal, "The Guide to Beating a Heart Attack." I initially wrote about surviving a heart attack (myocardial infarction {MI} is the medical term). Next I wanted to turn toward the prevention side.

I first found the Interheart study's article from 2004, "Nine modifiable risk factors predict 90% of acute MI." The study followed 29,000 people from 262 sites in 52 countries and concluded that the common belief that half of heart attacks can be predicted was clearly an underestimate.

The research group found the same impact of the nine variables everywhere in the world: abnormal blood lipids (fats, like cholesterol) and smoking were at the top of their list. Then came diabetes, high blood pressure, abdominal obesity, stress & depression, exercise, diet and alcohol intake.

I was used to measuring cholesterol and its HDL (so-called good cholesterol)  and LDL (bad cholesterol) components. This study actually used a more sophisticated lipid approach.

They measured the ratios of  the proteins that bind to and carry fats, apolipoproteins A and B. APOA is associated with HDL lipids while APOB is said to unlock the door to cells and in doing so acts as an unwelcome delivery van for cholesterol. When present in high levels, APOB can lead to plaque formation in blood vessels and an increased risk of coronary heart disease (CHD).

They also found some good news: as expected, eating fruits and vegetables daily, exercising and perhaps moderate alcohol intake were associated with lower risks of CHD. Again this was true everywhere in the world.

The WSJ article mentioned that hospital admissions for heart attacks had actually decreased among the elderly; these nine factors were better predictors in younger groups. What can be done to stop the looming specter of CHD among our younger population?

The CDC examined the parameters in a recent online article titled "A Growing Problem." One issue was "screen time." Our kids eight to eighteen average four an a half hours a day watching TV and three more on cell phones, movies, computers and video games. I even read an article about a two-year-old whose parents think learns a lot from their iPad. Maybe so, but how much exercise does that kid (and his older compatriots) get?

The CDC feels there is a dearth of quality physical activity in our schools; as of 2009 only a third of them provided daily PE for our kids. And after they leave school or when they're on vacation, many don't have safe access to biking, hiking, running, playing areas and trails.

Somerville chose healthier food in their schools

One Massachusetts community, Somerville, has gotten attention for their anti-obesity integrated program, "Shape Up Sommerville"  (You can watch the thirteen minute PBS special on their community-wide progress). The Robert Wood Johnson Foundation is attempting to help similar programs get started across the country, especially focusing on childhood obesity.

Recently I heard a NPR comment that caught my attention. If we don't do something to stop the epidemic of childhood obesity, we'll soon be seeing CHD rates soar in people in their 20s and 30s and maybe even younger.

A French researcher said, "Mankind is doing a good job of killing himself."

We need to try new approaches to help our kids. The Somerville plan sound like a good place to start.




Surviving, or better still, preventing heart attacks: Part 1: After it happens

Friday, May 18th, 2012

Heart attacks frequently cause sudden cardiac arrest

The April 17, 2012 edition of The Wall Street Journal had an article titled "The Guide to Beating a Heart Attack." It had both good news and bad: since the 1970s the annual number of American deaths from heart attacks (the "med-speak" term is myocardial infarction or MI) has diminished by three fourths; on the other hand nearly a million of us will have an MI this year and many of those will die.The National Vital Statistics Reports estimate for 2010 was 595,000 deaths from heart disease (of all kinds)  and the Seattle-King County 2012 estimate is 480,000 adults dying from an MI or its complications.

A quarter million die from sudden cardiac arrest (SCA) and the majority of those happen in a non-hospital location. Only 7.6% of people who  have an SCA outside a hospital survive to be discharged to home. This figure varies markedly according to where you live. If you happen to reside in Rochester, NY, your odds are much better. Bystander-witnessed cardiac arrest victims there who have the typical heart rhythm disorder that leads to sudden cardiac arrest (it's usually due to a chaotic quivering called ventricular fibrillation{VF}), have a 50% chance of survival to discharge from the hospital.

My mother, as I've mentioned before, was one of the fortunate ones. She didn't live in Rochester or in the Seattle area which also has a superb track record.  But she had a bystander-witnessed event, got prompt CPR and a rapid response from a trained Advanced Cardiac Life Support (ACLS) team, and lived another 16 years.

The Seattle-King County concept is termed "Community Responder CPR-AED." They knew that most people who die from SCA have VF and the only "cure" was to use a defibrillator. Most non-medical people wouldn't be able to operate the complex gadgets used in hospitals. The answer was the AED, an automated external defibrillator developed nearly twenty years ago.

The American Heart Association" Science Advisory commentary on AED use by non-medical people has a four-point program for out-of-hospital SCA: early recognition followed by a 911 call; early bystander-performed CPR; early AED use and then early ACLS.

look for this sign

They included several extra points I hadn't thought about, having always performed CPR-defibrillation & ACLS in hospital settings. Early CPR increase the possibility that defibrillation will stop VF and the heart will then resume its normal rhythm; it does so while providing blood flow to the brain as well as the to heart. And all the AED does is stop the VF abnormal heart rhythm enabling the heart to restart normal beating, but the heart rate may be slow to begin with, so CPR may be necessary for several more minutes.

Early CPR also increases overall survival rates; if it's not being provided, every minute between the patient's collapse and defibrillation lowered that rate by 4-6%.

Given all that, one of the first things the state of Washington did was to pass a law granting immunity from civil liability for any person (or entity) who acquires a defibrillator. Then they started wide-spread CPR and AED training (learning to use an AED is easier than learning CPR) and markedly increased their paramedic numbers.

The life-saving results have been very impressive. My question now is whether to buy an AED for our home.


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.