Our Newest Emerging Global Traveler: Chikungunya

In early December of 2013 while scanning my Twitter feed I spotted a very curious retweet from Helen Branswell (@HelenBranswell), a medical reporter for the Canadian Press who is a great source of updates on the spread of the MERS virus in the Middle East. What caught my eye was that Helen was not posting about MERS or Influenza (another topic she frequently tweets about) but she was retweeting a story about an African fever virus called Chikungunya and it wasn’t in Africa, it was in St. Martin in the Caribbean.

My first thought was this was an interesting curiosity, a few folks had traveled to Africa on holiday, been bitten by the mosquitos that were infected with the virus and traveled back home incubating the virus. This sort of little accidental infection limited to a few individuals occurs

Sometimes we bring back a little more than we bargain for

routinely in our age of rapid travel so it is not uncommon these exotic sounding diseases get a short excursion from their natural habitat, but the conditions in the other parts of the world usually prevent them from becoming established. So although the report of 10 people infected with Chikungunya on a Caribbean Island was a bit unusual, at first I thought this would just be another short story for public health history archives.

It's Complicated!

But ten people is an interesting cluster to me and just a little quick reading of some of the recent research on this virus had me reconsidering my assumption. I hadn’t thought of Chikungunya since graduate school virology class in the 80s so I was surprised to learn a lot of things have changed in the story of how this disease is transmitted since then. Airline industry experts are constantly telling us, “it is never just one thing that brings down an airplane, it is a series of problems or malfunctions that result in a crash”. This once obscure African fever, Chikungunya has a similarly framed story. It wasn’t just any one particular event that led it out of Africa, and clearly it is now well established outside of Africa. Some very fascinating evolutionary events involving a virus and the mosquitos that transmit it intersected with changing human behaviors and practices. As a result the course of this virus has altered remarkably and Chikungunya is on the move.

Really, The Name Says It All

From the Makonde language Chikungunya translates into English as, “that which bends up” and in Swahili the word means “the illness of the bended walker”. The name refers to the painful arthritic condition that is associated with a disease that typically persists for weeks, can last for months and on occasion even years following an acute bout with this virus. There is no vaccination to prevent it and there are no drugs to specifically treat it, the symptoms including high fever and extreme joint pain are managed until the illness runs its course. It is rarely fatal, but it often makes the aching feverish patient wish they would die, at least in the short-term.  

The Chikungunya Virus (CHIKV) was first detected in 1952 in the African Makonde Plateau, an area on the border of Mozambique and Tanzania. It is one of those “fever” viruses that we tend to associate with central Africa and I had assumed it was safely confined to central Africa, but CHIKV has been on the march and the story of this journey is pretty amazing. For most of its history CHIKV was confined to the forest in the central portion of east Africa. It’s a virus and just like all viruses it seems to have one only one purpose. It wants to make more copies of itself. That is how a virus species survives. But unlike most other forms of life that we classify as living, viruses are not capable of making more viruses on their own, they must have help. 

Viruses Really Can't Be Left On Their Own

Viruses require a living organism to act as their host. All plants and animals and even many bacteria and fungi are known to be susceptible to viruses. Not just any animal or plant will do for a particular species of virus, viruses for the most part are very picky about their specific host. A virus is considered to be an obligate intracellular parasite meaning it is dependent on that specific host that it is compatible with in order to survive and produce more copies of itself.

Although viruses require a host, most potential hosts usually don’t want to house a virus. For the most part viruses make lousy guests. When a virus enters a host, it finds the cells that it needs to make more copies of itself and if it can get into those cells usually the problems for the host begin pretty quickly and outweigh any advantages of having a viral guest. When the virus enters a suitable host cell it makes the machinery in the cell stop performing whatever function it is supposed to be conducting for the host and it reprograms the cell to start making more copies of the virus. Essentially a hijacking has occurred and the essential functions that cell had been providing for the host are discontinued. That infected cell has been converted into a little viral factory that pumps out multiple copies of viruses that in turn infect more cells and the process keeps spreading.

This will only keep happening for a defined period of time. Either the host’s immune system kicks in and starts fighting back and will destroy the virus or the virus will keep working the enslaved cells of the host forcing them to make viruses until they are exhausted and destroyed. If enough damage is done the host finally dies. Either of these outcomes is no good for the virus if is remains trapped inside the host, so the virus must have an escape plan. Once infected, a host is only suitable for a limited period of time so timing is very important on the virus’s part. If the species is to survive it must get out of this host and into another one. That’s the role of the mosquito in this “vector transmission” (or spread if you prefer) of CHIKV. Although CHIKV doesn’t usually kill its host, the virus must get out of that host and into another host before the immune system gets wise to it and destroys it. The virus gets helicoptered (actually mosquitoed) out of one host and into another host to start virus production all over again. This insures survival of the virus.

Chikungunya Forms A Partnership

So probably thousands, maybe millions of years ago CHIKV and nature worked out a very suitable cycle that created a complex but efficient arrangement between nonhuman primates (apes), a specific species of mosquito called Aedes aegypti (A. aegypti) and CHIKV. These apes were once plentiful in the east central African forest, the female mosquito needed the blood of the ape to nourish the eggs that would become her offspring and the virus figured a way to attach and survive in that particular mosquito species and when she fed on an ape infected with CHIKV, the virus would slip into the mosquito with the blood meal and would remain in the midgut of the mosquito. When the mosquito later fed on an uninfected ape she deposited the virus while she fed and the virus soon setup viral production in this new host ape. This cycle worked very efficiently until humans entered the picture. Successful transmission of a virus requires a little genetic level trickery the part of the virus that involves the proteins on the virus surface. The first trick is that its proteins must be compatible with the proteins in the mosquito so that the mosquito could actually tolerate its presence. Otherwise the mosquito’s immune system would destroy the virus when it realized it was “foreign to its body”. The viral proteins had to be sufficiently compatible so that the mosquito wouldn’t consider it a threat. So some sort of détente is achieved between the mosquito’s immune system and the virus so that the virus doesn’t harm the mosquito.  Then it had to perform some similar magic once it got into the host. It had to trick the ape’s immune system into thinking it wasn’t a problem so the proteins on the virus had to also be able to evade the ape’s immune protections in order to penetrate a suitable cell. Once inside the cell, the hijacking begins. The virus knows it only has a limited window of opportunity to do its work. The host immune system is going to eventually figure out there is an intruder and when the war to rid the ape of the virus starts it will be severe. There is no time to waste, the cell is forced to begin production and the pace is fast. The virus has to prepare to get into that escape mosquito as soon as it presents itself.

Humans Enter the Equation

The intrusions of humans into this non-human dominated forest began to interrupt this long established cycle. The mosquitos began to try to feed on these new primates, the humans. After all, they still required a blood source for their offspring so a mutation in proteins of the mosquitos meant strains of A. aegypti mosquitos that lived off human blood began circulating in the forest alongside strains of the species that fed off traditional non-human primates. At first when those mosquitos dumped the CHIKV virus into humans the virus was destroyed because the human immune systems recognized those surface proteins as “foreign”. As urban settlements began to establish themselves in the interior, the population of non-human primates began to dwindle so more and more frequently humans were being bitten by CHIKV infected mosquitos. Viruses are always making mutations, most don’t survive, but eventually mutations that resulted in proteins that fooled the human immune system were created. It was as if nature was doing market research and preparing for a consumer shift. The forest population switch

Transmission cycle for Chikungunya between humans

from non-primate to humans in the forest was a challenge for CHIKV. But nature is resourceful. The CHIKV virus also began to evolve itself. The new mutations that infected humans were becoming established and circulated along with the strains that still fed on apes as long as they were available. By the mid part of the 20^th century there were multiple small outbreaks where the CHIKV was transmitted to humans through the bites of the mosquitos.

The protein structures on the surface of the virus altered and the strains that contained proteins that allowed for the attachment of human cells began to thrive. This meant that those infrequent human outbreaks could become more frequent since the mosquitos began to circulate more virus capable of attacking humans more frequently. Still the CHIKV mosquito to human transmission was confined to this area of the African continent because the only mosquito that was capable of transmitting CHIKV was the A. aegypti. A new successful balance had been obtained, the virus had found a means to survive and thrive in its cozy little corner of the world. The infected mosquitos and the infected hosts (both apes and human) were isolated enough that the disease would run its course in this new cycle without having a real opportunity to travel. Humans had gone to great lengths to keep the A. aegypti mosquito isolated.

The Mosquito With The Sordid Past

By the discovery of the CHIKV in the 1950s, A. aegypti was well known to be a vector for some pretty nasty viruses besides CHIKV. The Yellow Fever Commission led by Walter Reed had identified A. aegypti as the vector for Yellow Fever at the beginning of the 20^th century before it had even been proven that Yellow Fever was caused by a virus and since that time the A. aegypti mosquito had been revealed to be the vector for Dengue Fever, Malaria and was suspected to transmit a number of other diseases. For much of the first half of the 20^th century impressive public health campaigns were carried out to shrink the habitats of the A. aegypti mosquitos. The species had been widely distributed around the world but sanitation campaigns to reduce their numbers in urban areas were very effective along with powerful pesticides. The population was well controlled and as a result, the A. aegypti mosquitos began to disappear from much of the urban world and along with it those great epidemics of Yellow Fever disappeared from North American and European cities. While small pockets of A. aegypti mosquitos remained in swamps and marshes in some of those areas, those populations were not infected with the Yellow Fever Virus. Yellow Fever was now primarily confined back into the sparsely inhabited forests of Africa and South America where it once again primarily circulated between mosquitos and non-human primates, only occasionally making its way into the urban areas of those regions. When A. aegypti was contained so were the other diseases it transmitted such as Malaria and CHIKV.

But nature is determined to have its way. Viruses continue to evolve and these resulting mutations will occasionally persist. The proteins that make up a virus determine its behavior. When those proteins alter, so do the behaviors. It was an alteration in those proteins that first allowed the CHIKV to infect humans in addition to the original non-human primates. Humans played a key role in driving another protein change in this balance when their behaviors shifted the mosquito populations in this area of the world. When the A. aegypti population began to shrink, nature once again kicked the CHIKV into survival mode, and the search for a new mosquito host began. What was actually happening was at some point the humans and the apes were being bitten more and more frequently by the growing populations of the new species of mosquitos and less and less often by the shrinking numbers of the displaced A. aegypti. Nature is resourceful, so it was inevitable mutations that would survive in the new species of mosquito would arise as they begin to take over the territory.

When You Block Her Path, Nature Finds A Way: A New Vector Emerges

While we were busy ridding the world of A. aegypti and eliminating all those nasty epidemics associated with it, we completely ignored its “little cousin” Aedes Albopictus. It turns out this was an epic oversight on our part. A. aegypti was indeed a nuisance to us, but it was usually because we invaded the wet and boggy areas that it had populated first and we then intruded. It didn’t want to live with us, we took its territory. However it turns out A. Albopictus enjoys our company, actually thrives in our midst. It takes advantage of the opportunities that we provide for it in our environment. Just about any little moist area that we create in our urban world, it will use. It is particularly bothersome to us because unlike A. aegypti who prefers to bite from dusk until dawn, A. Albopictus feeds on us all day long. It earned itself a common nickname that is very descriptive of its appearance and some say its attitude, the Asian Tiger Mosquito. Tiger because of the stripes it sports and some would say its aggressive biting behavior, but Asian because it was found exclusively in Southeast Asia until it found how desirable it was to live and travel with us just about wherever we go. Once again, it was not a single event, but a combination of factors that permitted the spread of A. Albopictus from Asia.

Our Short Collective Memory Sets Us Up for Disaster

As it happens so often, once we stopped having those epidemics of Yellow Fever and Malaria of biblical proportions the traumas of these outbreaks left our collective memories and we began to tire of spending money on sanitation and public health programs. If we don’t see a problem, it really just doesn’t exist. We largely stopped our public mosquito eradication and control programs as a way to “save money”. Populations of A. aegypti began to recover. Most of them were absent of the viruses that causes the diseases and the parasites that caused Malaria, but the vector (mosquito) populations did rebound.

Meanwhile, A. Albopictus got its chance to spread thanks to our consumption and wasteful lifestyle as humans and our enterprising ways to efficiently ship both our consumer goods and our waste products. By the 1960s A. Albopictus had been detected in India and in the Pacific Ocean region. This initial venture out of Southeast Asia was most likely aboard ships loaded with goods for trading. In 1979 it was discovered to have migrated to Albania among goods shipped from Japan. It then found its way to the United States at the Port of Houston in 1985 among a shipment of used tires from Asia. It was not confined there, it spread throughout most of the Southeastern US and even as far up the eastern seaboard as the coast of Maine. It was soon discovered that the enormous quantity of used tires being shipped around the world was playing a very efficient role in transporting A. Albopictus to new areas where it had never been seen. In 1991 it was exported from the U.S with used tires shipped from Georgia to Italy and it spread from there throughout the Mediterranean and Europe, even into the Swiss Alps. This

species is capable of wintering well in our environment and the eggs survive freezing temperatures. In 1991 it also made its way into Africa first being detected in Nigeria in used tires shipped from Japan.

When the protein changes occurred that allowed CHIKV to begin using A. Albopictus as a vector between humans, the CHIKV had at last found its ride out of the forest and its means to transition itself not just into a world traveler, but into a global resident. As different strains of A. Albopictus began to be established in different parts of the world, we began to realize this might be an efficient transportation network for many previously isolated diseases.

As the populations of A. Albopictus began to thrive in Africa, studies revealed that African strains of the species were now very competent vectors for many viruses that had previously been exclusively seen in the native populations of species such as A. aegypti. These included Yellow Fever, Dengue Fever, Rift Valley Fever, West Nile Virus and CHIKV. Researchers in Nigeria also noted that A. Albopictus was becoming well established globally and was rapidly displacing A. aegypti as the dominant mosquito in many areas. Its more aggressive nature and hardiness could mean that the risk of these diseases spreading farther and faster was a real possibility.

Old tires may no longer transport us but they suit mosquitos well

The viruses were changing and their vectors were changing. Our moving into their habitats had altered their habits and our introducing our inventions and waste products had altered their behaviors. It’s ironic that when tires cease to function as transportation for us, they have become an efficient vehicle for transporting mosquitos.

It’s never a quick or simple story

Not all the strains of the viruses have evolved in the same manner. Neither have all the mosquitos. Researchers have concluded that some strains of A. Albopictus found in North American have evolved into becoming competent vectors capable of transmitting Yellow Fever and Dengue Fever under certain environmental conditions. So now apparently at least some of them have evolved to be able to effectively transmit CHIKV in the Caribbean area of St. Martin. The case toll has climbed. The outbreak of ten initial cases reported in St. Martin in December of 2013 has now escalated into over 700 cases of CHIKV being reported in eight different Caribbean area islands and countries as of late January 2014 and 498 new cases were reported in one week alone in January.  

The virus is now known to be set up and circulating in the A. Albopictus mosquito population in the Caribbean region and the mosquitos are transmitting it as they bite infected people and then next feed on uninfected and susceptible people. This means for us in Florida that CHIKV is only a couple of days away by ship and a few hours away by air from us and our huge population of A. Albopictus mosquitos. If an infected person disembarks here and is bitten by our local A. Albopictus it is indeed possible for them to start the cycle of transmission here if the local population of mosquitos has evolved to host the virus. But is this likely to occur? Many experts think it can, but studies are still underway to determine if the various strains of A. Albopictus here in the US can transmit CHIKV, and if they can will environmental conditions be favorable for this to happen.

Science To The Rescue

I was curious to learn more about these studies of the A. Albopictus and transmission risks. As a kid I read and marveled at those stories about the experiments conducted by dashing public health heroes such as Carlos Finlay, Jesse Lazear, Walter Reed and my personal hometown favorite son from Mobile, William Gorgas as well as many others who unraveled secrets about disease transmission. There were stories of scientists who frequently became ill with the diseases they studied, more than a few lost their lives. Today scientists realize the story of transmission is even more complicated than envisioned by those early researchers. There are a number of factors that are involved before a virus can establish itself in a new geographic region. In the case of CHIKV, these include more than just the presence of the appropriate mosquito acting as its vector. The environment and the climate both play roles in establishing the vector as well as the virus.

Transmitting the virus to the mosquito the slow way

Research techniques and tools have certainly advanced since those early 20^th century pioneers did their extraordinary groundbreaking work, but one study I reviewed described a technique that I had never even imagined and it caught my interest straight away. That technique is referred to as the mosquito enema. Obviously studying the various strains of mosquitos as well as the various strains of virus is painstaking and complicated work with many unique challenges, but learning that scientists were actually capable of giving a mosquito an enema was as fascinating to me as the reason they were doing it.

Today's rapid technique for infecting a mosquito

So, why give the mosquito an enema? It seems that the method in which the mosquitos being infected with CHIKV can influence the accuracy of transmission predictions. We’ve come a long way from the days of feeding mosquitos a virus induced blood meal where volunteers stick their arms into mosquito filled cages. That was an effective but slow research method. In addition to the oral feeding of the mosquito with virus infected blood, scientists learned that work could proceed more efficiently by administering the CHIKV virus by either intrathoracic injection or by administering the virus via an enema. It seems that the enema route offers the advantage of getting the virus into the midgut faster than the oral route and without the introduction of a wound caused by the injection. Some rather intricate methods are necessary to get a better understanding of which mosquitos can transmit which viruses and where. It seems in order to obtain meaningful data on transmission, some very precise laboratory techniques as well as unique skills are required to conduct this research.

Where in the World Is Chikungunya Headed Next?

So where are we today? Well in the case of Florida, many researchers have concluded we probably have cause for concern. Already in our extreme southern counties the A. aegypti population has rebounded and they are transmitting Dengue Fever. The cases of locally acquired human transmission of Dengue have been rising for several years. But A. aegypti is the dominant mosquito in only specific parts of a few south Florida counties. All of the other counties in Florida are dominated by A. Albopictus. It seems our little Asian Tiger friend is just about everywhere in our state. 

In 2008, a team led by Michael Reiskind from LSU published their findings after studying various strains of Aedes mosquitos in the US and their conclusions were that the populations of both A. aegypti and A. Albopictus in Florida are capable of transmitting CHIKV. Other studies have demonstrated the climate in south Florida may increase the risks for CHIKV establishing itself here rather than other areas of the US where the virus may also gain a point of entry.

The red shaded areas indicate U.S. geography there A. Albopictus is established. 

In other areas of the US, the large swings in seasonal temperatures make it unlikely the virus will be able to be transmitted year round. However the smaller temperature swings between seasons in south Florida increases the likelihood that the virus could be successfully vectored by the mosquitos there. This increases the possibility of year round transmission of CHIKV in south Florida where there is so much human year round outdoor activity.

It’s not a forgone conclusion that we will see CHIKV establish itself in south Florida, but when we examine the journey of the virus and the mosquito, it doesn’t seem such a far stretch any longer. Already there are calls for an increased vigilance of our mosquito populations and the appropriation of funding to increase eradication programs. In the Florida Keys the use of genetically modified mosquitos to curve the population of A. aegypti that has been transmitting Dengue is being studied but is meeting a lot of opposition from anti-GMO groups. No one doubts that CHIKV is on the move again, it will be interesting to see if Florida is in fact a new destination. 

Recommended Sources For Additional Chikungunya Information:

Chikungunya Virus Net.com http://www.chikungunyavirusnet.com/

Centers for Diseases Control and Prevention (CDC.gov)  http://www.cdc.gov/chikungunya/pdfs/CHIKV_VectorControl.pdf

European Centre for Disease Prevention and Control http://www.ecdc.europa.eu/en/Pages/home.aspx

Send in the Orphans - A brief history of informed consent!

Most of us accept informed consent as routine and automatic. But given our track record in looking out for others outside our own intimate group, it serves us well to conduct a reality check on occasion.

Throughout history we can find numerous instances where the people in control have preyed on the weak or the powerless. Many people know the stories of the Nazi atrocities during the 1930s and 1940s and the experiments the Japanese conducted on the Allied POWs during World War II, but the use of uninformed or powerless individuals in medical experimentation has been going on for centuries. That still doesn’t make it right, but I have to say I have been more than a little fascinated as I learned just what we humans have done to others “for the greater good of the collective” throughout our history.

A Progressive Champion steps forward

When Smallpox was the scourge of the earth long before vaccination was developed, the practice of variolation was the accepted prophylaxis against Smallpox in much of Asia. Smallpox scaring and complications were common throughout Europe and the mortality rate was significant as well. Lady Mary Worley Mantagu is often credited for introducing variolation to Britain. Her husband was posted as Ambassador to the Ottoman Empire (Turkey today) and while stationed in Constantinople against her husband’s wishes she had their son variolated. Lady Mary was apparently severely scarred from Smallpox herself and in fact had no eyelashes as a result of her own illness and was determined her children would not suffer as she had. She also was instrumental in persuading many of her friends and family to undergo variolation for their children.

A Process is Born

King George and Princess of Wales Caroline, the reigning monarchs of England were intrigued about the success of the procedure and of course wanted the Royal Princesses protected. But first they had the Royal Surgeon make certain it was in fact safe for the young princesses. To insure the safety of the Royal Princesses the Royal Surgeon first had six condemned and jailed prisoners (male and female) variolated. He promised them amnesty if they survived. None of them died. This was good but not quite good enough for the Royal Highnesses. That was apparently a “Phase I” trial. Today clinical trials are often accompanied by catchy marketing generated names that resonate with the Pharmaceutical company or sponsoring entity and a lot of time and expense goes into choosing that catchy name and clever acronym. I think the most apt name for this next Phase II trial could have been “send in the orphans”.

Ten orphans from the St. James Orphans Asylum were selected and variolated. When they all lived The Princess Caroline decided the procedure was safe enough for the young Princesses. Still Variolation was not without problems, some studies show the death rate from the procedure to be as high as 5%, less than that of smallpox (15 – 20%) but not exactly odds that assured people.

The good doctor did what?

The celebrated Jenner vaccine protocol would have had certainly raised eyebrows today. Edward Jenner was a country doctor, but he was educated in London’s St. Georges Hospital under the famous surgeon of the day, Dr. John Hunter. Jenner was a keen observer of nature and was convinced of the prevailing theory of the time that people who recovered from the very benign illness of Cowpox never got Smallpox. When a local milkmaid named Sarah Nelmes came to see him with an obvious case of Cowpox sores on her hands Jenner saw his chance. Somehow he managed to convince a local farmer named Phipps to let him inoculate his son with Cowpox assuring him the boy would never suffer from Smallpox. Somewhat surprisingly the farmer agreed so Jenner inoculated young James who was six years old by making two cuts in his arm and pouring a vial of the Cowpox puss into the cuts. Young James came down with a mild case of Cowpox and quickly and quite nicely recovered.

Then came Jenner’s “Phase II” and if we were to name this study today it would be called “WTF RU NUTZ?”. Six weeks after pouring the cowpox into the kid’s cuts Jenner took puss from a dying Smallpox victim and again made an incision in young James arm and poured in the Smallpox puss this time. Whoa! Did the farmer sign up for this part of the experiment? Fortunately Jenner’s theory was right and young James did not come down with Smallpox. Had young James contracted Smallpox and died, Jenner would surely have faced a murder trial. If an IRB were to be presented with this proposal today their eyes would pop out of their head! The cynic in me actually can’t help but wonder if Jenner didn’t “have the goods” on the good farmer Phipps because I cannot imagine a father even considering such an action.

Meanwhile - back at the orphanage

Even after Jenner’s vaccine to prevent Smallpox was discovered we didn’t end the use of orphans as medical tools. The vaccine was effective, but how did it get manufactured? It was discovered that “arm to arm” inoculation was very effective. That meant once a person had the Cowpox virus inoculated into their body, it could then be extracted and inoculated into another person. Convenient since the only container for a human vaccine at that time was the human body. No such thing as a vial, ampoule or a syringe. Why orphans? It seems unbelievable today but orphans were considered to be the perfect solution. Society had fed and housed them, no one championed their cause. They were less troublesome than convicts (the other disposible group of the day).Usually you just had to have a nun watch over the orphans as opposed to guards, weapons and restraints for convicts.It really simplified that whole “chain of custody” process. Orphans, the perfect biological drug containers!

Not just an English practice

Next came the Balmis- Savony Expedition sponsored by another Royal House. King Charles IV of Spain had lost a son to Smallpox and announced that all the Spanish Colonies of America and Asia would in fact begin a vaccination program using the Jenner vaccine to wipe out Smallpox. The Balmis – Savony expedition was underway with orders to all civil and religious authorities to do what was necessary to insure vaccination of all the King’s subjects. Once again “queue the orphans”. A Royal edict was issued by Charles IV to take 20 children between ages 8 and 10 from La Coruna's Orphans' Home that had never had Smallpox. A plan was devised to pass the vaccine live, transmitting it from child to child as the skin lesions began to extrude lymph from Days 4 to 10 post-vaccination. The initial vaccination was performed in Madrid using 5 orphans who were sequentially inoculated on the way to La Coruna.

The ship was loaded with 21 orphans (along with one unlucky Nun) and the orphans were inoculated sequentially throughout the voyage to keep the vaccine alive until they reached their first stop – Puerto Rico and then apparently the orphans were systematically replaced with local orphans as the voyage worked its way through the Spanish colonies throughout the Caribbean and South American. Balmis picked up 25 fresh orphans in Mexico to transport the vaccine across the Pacific and ultimately on to Asia.

Fortunately we have less intrusive methods of transporting vaccines today. Syringes and vials immediately come to mind. Still, given our nature to take shortcuts and save costs as well as our tendency to use the subjects of convenience, I think history (ancient and recent) has provided us with a lot of good reasons for enhanced FDA oversight as well as a strong IRB process.

Regulations and regulators, considering our history, I am very much in favor of them!

Auto-correct "The Big Miss"

I have been swearing at my iPhone for weeks because I keep forgetting to see what ridiculous auto-corrections it is performing when I am texting or composing emails. For some reason I just cannot remember to look and review before I push send. Actually that is not entirely true,I know the reason ..it is because it is so awkward and frustrating to make a correction on the little screen I had rather just not know it was there and just assume it is perfectly composed and send it.

Today, I got to thinking about why such a useful feature is actually a curse and I realized the answer after I spent hours looking over 200 PowerPoint Slides in 3 decks I was creating where each time the program "assisted me" by changing "EHR" to "her".

There needs to be some simple logic driven way to find the function in these programs to let the software know I have not mispelled the damned word 600 times. I actually want to use that word. It is not like spell check where you are offered polite choices by a nice software driven assist. You can add the word to the dictionary, say "no thank you, leave it alone just this once" or say "thank you I am glad you caught that mistake Mr. Microsoft."

Auto-correct is spell check's evil twin. Auto-correct is like a condescending acquaintance who just presumes they know the best way. Yes, that's it .... I think auto-correct is like one of those self-righteous smugs who always think they know the best way to do everything no matter what and never look for input because they think they are just too damned perfect. Note to self: Let's do some market research and see how many senior executives have the middle name "auto-check". I suspect the study "N" will be quite significant (and that is not a term we use lightly in medical writing),

Like annoying people auto-check can be right on occasion but more times than not it is wrong and when it is wrong, it can be painful to all concerned. Like the time at Nabi when the IT Department made one of those system changes that wiped out all of our personal additions to our online dictionary. Care to guess what the autocorrect answer is to the unrecognized word "Nabi". It is "Nazi".

Just imagine my horror when I looked down and saw I was half-way through signing a stack of letters as the "Senior Director of Sales and Marketing for Nazi Biopharmaceuticals." Those letters went straight to shredder (thank God) instead of the mailroom. I had never been able to truly consider auto-correct a trusted tool and that experience sealed its fate for me. I declared it not just useless but evil. At this point I would disable it completely but I am guessing the feature for doing that is located somewhere in another dimension along with the "edit" autocorrect function. It just thinks itself too perfect for any manipulation on my part.

What a useless tool.

Then today I saw someone had an evenmore horrifying auto-correct incident that they posted online. Oh yes, auto-correct is not just annoying, it is down right evil.

I am so relieved to know it isnt just me.

Who needs regulations? We do!

Who needs regulations? We do! A few weeks ago most of us were caught unawares when Secretary of State Clinton and Secretary of Human Services Sebelius issued a statement apologizing for reprehensible medical experiments that the U.S. government conducted in Guatemala in the 1940s. They were apologizing for a Syphilis Study. Why did this sound more than vaguely familiar? It turns out that the same Public Health physician who was so instrumental in conducting the infamous Tuskegee Syphilis experiment also conducted an even more unethical experiment in Guatemala on Guatemalan citizens. The announcement was made and then ….nothing, we heard nothing else.

Lately I keep hearing a lot of noise from people about government regulations being overbearing and they toss about the charge we are becoming a “nanny” nation. Then something pops up like say an oil company that practically pollutes the entire Gulf of Mexico by cutting corners and ignoring regulations or a coal mine that considers them unnecessary. Or we discover everything from our drugs to our pet food have been contaminated by unscrupulous manufacturers. Then we scream, “Where were the regulators?” Face it, we need oversight. Humans always have and always will. Medical research is not an exception to that rule either. The Guatemala revelation is just the latest evidence that shows how important a strong Investigational Review Board (IRB) is to our clinical study process.

First, a quick review of a shameful story most people have at least heard about, the Tuskegee Syphilis Experiment. Black men living in the area around Tuskegee, Alabama who were diagnosed with Syphilis were identified and observed, but not told they were infected and were not treated for Syphilis for 40 years. This study was conducted from 1932 -1972 on 399 black men, most of whom were uneducated and living in poverty. These men were never told they had Syphilis. Even after Penicillin became the standard of care for treating Syphilis in 1947, this study did not end until it was leaked to the press in 1972. Many of these men passed Syphilis on to their wives and numerous children were born suffering from congenital Syphilis. The men were told they were being treated for “bad blood” and they were compensated with free medical exams, free meals and free burial insurance. This study is credited for being the catalyst that gave rise to the Institutional Review Boards that oversee all clinical trials today.

As heinous and unethical as the Tuskegee Experiment was, it pales in description to the Guatemala experiment. They didn’t just observe infected people, they intentionally infected people who had never had Syphilis with the Treponema bacterium that causes Syphilis in an attempt to induce the disease. This study was conducted for two years (1946 -1948). It was already well known by then that Syphilis could be cured with Penicillin but the purpose of this study was to see if Penicillin could prevent infection if it given immediately after exposure to Syphilis. As was the case in the Tuskegee study there was no informed consent from these teat subjects. The study population differed in that instead of using poor rural black citizens, the Guatemala study used hundreds of prisoners, men living in army barracks and male patients of mental hospitals. I am assuming they also got the free medical exams and meals since they were all institutionalized in some manner. No mention was made of burial insurance but there was one unusual “study perk”. Most participants appear to have been supplied with a syphilitic prostitute for their participation in the experiment. Still, it seems they were not able to induce a sufficiently high enough infection rate through the prostitution arm of the experiment so they resorted to even less conventional methods. Researcher’s notes reveal that the penises, forearms and faces of the men were abraded when “normal” exposure (i.e. inoculation by prostitution) failed. Next, a solution containing syphilitic bacteria was then poured directly onto the abraded surface. The records examined indicate that the infected patients were treated but the records do not indicate if they were cured or if they were even adequately treated.

Regulation and oversight, who needs them? We do!

Presenting a true American Hero - Dr. Frances Kelsey

The FDA – Who needs it? I say we do. Since beginning my career in the commercial side of medicine and laboratory science during the Carter Administration, I have been subject to FDA rules, policies and restrictions. Throughout these years it seems that any given project I am involved in the FDA is often invoked as the “obstacle” to preventing our “corporate success”. I have heard various versions of that accusation from people in almost every corporation that I have talked with throughout my career.

I just want to respectfully remind my colleagues, the FDA is not our enemy, without it our industry as we know it would not even exist. Do corporate goals get hindered on occasion by FDA process? Well of course they do, but in the name of keeping us and our industry safe. This is where Dr. Frances Kelsey enters the picture.

Dr. Kelsey at her home today

A key reason that American produced pharmaceuticals and blood products are considered the safest and most desired around the world is because of the oversight and regulations that are enforced by our FDA. It was grave mistakes as well as some selective actions and inactions by a few pharmaceutical corporations that gave the FDA the authority it needed to protect American consumers. These standards that were imposed on our industry in turn have made it one of the safest in the world today. The goal of the FDA is not to be a corporate roadblock, but it provides a huge safety net that protects citizens and by extension our pharmaceutical industry through monitoring and enforcing critical rules and regulations.

This week Dr. Margaret Hamburg, the FDA Commissioner, presented the first Kelsey Award to Dr. Frances Kelsey. Those of you who have sat through one of my Clinical Trials training classes may remember Frances Kelsey as a person who I hold up as an example of a true American hero (and by the way she immigrated to this country from Canada.)

Fifty years ago Dr. Kelsey was the FDA medical officer tasked with reviewing the application for Kevadon, the morning sickness drug that was to be launched in the U.S. by the William S Merrill Company. The drug was already widely used throughout Europe (and many other parts of the world) and Merrill was quite anxious to launch it in the U.S. so the application to the FDA was accompanied by much corporate and political pressure.

Dr. Kelsey was not impressed with the data submitted with the application and was very suspicious of her interactions with the Merrill officials when she attempted to get additional data. As a result Dr. Kelsey denied the approval of Kevadon which is actually better known today by its generic name, thalidomide. Dr. Kelsey held to her principles and as importantly despite intense pressure from Merrill officials and politicians she was backed by her superiors at the FDA. Thousands of children throughout Europe were born without limbs or with flipper-like arms and legs when their mothers took Kevadon. Because of Dr. Kelsey’s steadfast refusal to bend to the pressure of the Merrill executives and because her superiors at the FDA supported her position, the number of children affected with this severe birth defect in this country was exponentially smaller than throughout the world. Dr. Kelsey is often referred to these days as “The midwife of modern pharmaceutical regulation” because of her many contributions to the design of the clinical trial process and the roles she played in the events that resulted in empowering the FDA for our protection.


Children born with the "flipper syndrome" that was the result of thalidomide exposure.















"Flipper syndrome" victims of thalidomide as adults today

The Kelsey Award is going to be presented annually to an FDA staff member that is selected for outstanding public service. I am very pleased that this distinguished award will be named for Dr. Kelsey and I think it fitting she is to be the first recipient. Her example of courage as a government employee is one that we need to remember and celebrate.

So why do we need an FDA? For the pharmaceutical industry, it saves us from ourselves. If our pharmaceutical industry is to remain they envy of the world in terms of safety and efficacy we need to remember oversight and regulations are important for many reasons. We continue to demonstrate that self-regulation (both on the individual level and the corporate level) fall embarrassingly short of its goals. This phenomenon isn’t limited to the pharmaceutical industry. It is true for individual humans and corporations of all types. We are just not capable of adequate self-regulation. Oversight is required. So let’s face it, the Pharmaceutical industry and the FDA need each other. It is a symbiotic relationship that needs to be respected and encouraged to continue to serve the public as it was intended.

Thank you Dr. Frances Kelsey for setting an example for courage and integrity that can resonate with us all today.

Attached is a link to the New York Times story about Dr. Kelsey. It is a fascinating glimpse into the life, the career and the character of this truly amazing person who has played a key role in all of our lives today.

http://www.nytimes.com/2010/09/14/health/14kelsey.html




In 1962 President John F Kennedy presented Dr. Kelsey with the Distinguished Civilian Service Medal for her role in preventing thousands of babies from suffering the devastating effects of thalidomide.Whether we are a patient, a provider or a practitioner in the medical field our lives have all been touched in some way by the contributions of Dr. Frances Kelsey and her service to us all should never be forgotten.

Florida's newest arrival: Dengue Fever

Here it is only July and in Florida we have already been given enough to worry our heads about for the entire year. We lead the nation in unemployment and housing foreclosures. The prognosticators started warning us early this year that this will be a record hurricane season (State Farm apparently responded to this prediction by promptly canceling my homeowners policy after 31 years!) and we have been told to prepare for the onslaught of oil from the BP disaster that will reach our beaches and estuaries in one or more of several (all heinous) forms that include such names as mousse, tar balls and tar sticks. I kid you not, watching the evening forecast on the Mobile and Pensacola television stations during the weather segment they now announce which (if any) of these disgusting forms of oil can be expected by beachgoers on the following day. Thanks BP. Bastards!

So with all this on our minds perhaps we can be forgiven if we overlooked that little article reporting on observations by the CDC that was tucked in between the latest misbehaving elected officials and the newest examples of corporate criminal activity or unbelievable greed that fill the news. No wonder most of us overlooked the fact that a dozen cases of Dengue Fever were uncovered in Key West, Florida. But as someone who contracted Dengue while working and traveling in Southeast Asia it caught my attention. I learned quickly during my bout why it is called “Breakbone Fever” in much of the world. The persistent high fevers and excruciating joint pains I experienced made it one of the most unpleasant experiences of my life. So when the CDC announced this week that their epidemiological survey has determined that over 5% of all the Key West residents have antibodies to Dengue Fever I realized, “Florida, we got a problem”.

Even if people have heard of it, very few know how to pronounce it (den’ gee). Now is the time to take a few minutes to sit down and learn a few useful facts. The most important of which is “remain calm”. We all know a huge media spin is about to accompany this revelation so a few facts will help head off irrational fear. The CDC tells us over 5% of the people in Key West (over a thousand) were exposed to or infected by the virus that causes Dengue, yet less than 100 have actually sought medical care. That tells us that the majority of the people have very mild infections. That’s the good news part. Still it is of little comfort if you are one of the ones who experience a really bad case of Dengue and right now the reasons around why who gets which type of illness are pretty hypothetical. The illness can range from very mild to some wicked complications that include Dengue Hemorraghic Fever (DHF) to Dengue Shock Syndrome (DSS). With names like that, you know they can’t be good.

I was feeling a bit smug in thinking that since I have previously had Dengue I will just be sitting on the sidelines as this epidemic travels through the parts. Then I did a quick review of those CDC fact sheets and learned there are actually four types of Dengue (named 1 -4) and they are so named because there are 4 different viruses that can cause Dengue and if you contract one you still are vulnerable to the other three. I was not pleased to learn I can theoretically experience this disease 4 times. I was even less pleased to learn that when you have it a second time it ups your chances of experiencing DHF or DSS significantly.

It is important to remember that this disease is transmitted by the bite of an infected mosquito. We don’t give it to each other. It has been shown to be transmitted via donor blood and human organ transplantation so the CDC has already begun taking proper measures with the appropriate industries and agencies to safe guard those practices. Let’s remember we cannot contract the disease directly from each other. It requires the mosquito to bite an infected person, incubate the virus and then transmit it to a healthy person in a subsequent bite. The mosquito vector is the key here. And it is not just any species of mosquito.

What we need to do now is make sure we take proper precautions to avoid mosquito bites. The mosquito that carries this disease is a pesky little mosquito that just loves to live around us, our old friend Aedes aegypti. No it couldn’t be one of those annoying but not usually found in our backyard mosquitoes that you only encounter in the Everglades. It is transmitted by ae. aegypti who has developed a fondness for living in the little splashes of water that we provide around our homes when gutters are not properly cleaned, or empty flower pots accumulate around the back beside the air conditioners, etc. But these days with all the abandoned and foreclosed properties, we have an unprecedented supply of incubators in our communities from small puddles in a low area of an unused patio to an abandoned backyard pool. The conditions are ripe for ae. aegypti in our communities like never before.

The link below to the CDC site contains some excellent information on Dengue including transmission, signs and symptoms and most importantly prevention. Oh, by the way, there is no vaccination for the virus and no specific treatment for the disease. Miami Dade health officials are already investigating the first suspected cases there. Since ae. aegypti is a dominant mosquito throughout urbanized areas of southern Florida we will most likely see the virus spread through our counties here in south Florida if we are not vigilant in reducing the mosquito habit in our yards and communities and if we fail to take proper precautions to avoid being bitten. It will be harder for the virus to establish itself in other parts of the U.S. because the ae. aegypti mosquito has all but been wiped out by the Asian Tiger Mosquito that arrived in the 1980s and began to crowd out ae. aegypti everywhere in the U.S. except south Florida. Lucky us.

So even if the BP oil does manage to avoid our south Florida coasts, the prospects of vacationers returning to their homes with a tropical disease aquired on a jaunt to Florida is not going to do anything to help our tourist industry. In the name of good health and a healthy economy it makes sense to educate ourselves on how to keep this disease at bay and contain its spread.

I encourage you to take a quick read of the CDC fact sheets so that you arm yourself with accurate information so that you can increase your chances of avoiding this unpleasant and possibly serious illness.

http://www.cdc.gov/Dengue/

A More Graphic Argument for Global Warming Concerns

Global warming. Nothing chills a room full of people quicker than when that topic comes up for discussion. The debate rages on. I have noticed a new tactic among many of the “deniers”. They have embraced a term that has entered the lexicon of late and made it their own. That term is “junk Science” and it tends to roll of their tongues just a little too easily and with ever increasing frequency. It is my observation that most people who use the term just don’t understand or like science. Since they have no use for it that they can see, they call it junk.

Many good people have tried many an effective means of trying to instill a knowledge or an appreciation of science where none exists. One of my favorite tools in this effort is the visual aid. One such as the following that starkly contrasts the past with the present.

You would think an image showing the early explorers arriving at the North Pole on foot with supplies pulled by dog teams displayed along side a present day picture of the North Pole would have some sort of impact. In 1909 it required a trek with a dog team to reach the North Pole and in 2009 you could send your parents there on a freestyle cruise ship. Something changed but this does not seem to cause worry amongst those so quick to dismiss the concept of global warming.

But I think I have just found something that might at least give them a moment’s pause. Scientists have shown us for years evidence of species relocating into new areas that were previously inhospitable to them because of the temperature or other climate restrictions. As the atmosphere warms, their ranges expand. We now have West Nile Virus endemic through the U.S. and it was never even reported there before 1990. We have seen Dengue Fever return to the U.S. for the first time in nearly a century. But this weekend I learned of a new pest that many people feel is moving closer to us. This one my denier friends you are going to want to hear about. You might even want to re-think your whole opposition to funding the Global Warming impact studies. I give you The Human Bot Fly.

Until this past weekend I had never heard of this insect. Trust me it will now be a long time before I forget it. This past weekend Juan Carlos asked me what I knew about Human Bot Fly infection. My response was, “Huh?”. One of his classmates had just posted on her Facebook page that she had recently returned from a vacation in the Yucatan and had contracted a Human Bot Fly infection that had just resulted in her having a larvae extracted from the back of her head. Once I gotten over the amazing revelation that there really are no boundaries as to what a person will post about themselves on a Facebook page we immediately went to Google for information and oh boy what we learned!

This fly is rather large and very distinctive looking in its appearance so problem solved, just avoid it. The more I read, the more I realized this is a nasty little creature. The female knows she must get her eggs into a host species if they are to survive. There are many different types of Bot flies. Some infect rodents, others cattle and there is a reason this particular one is called the Human Bot Fly. Yes, her eggs are destined for us. Because Bot flies realize they have no chance of installing their eggs into the unwilling host themselves, they have learned how to get others to do it for them. The female employs a process known as phoresis. Immediately after copulating she traps a mosquito or some other small blood feeding fly and she glues 50 or so eggs to their abdomen before she releases the captive. The relieved kidnap victim flies off and finds the appropriate host and when it begins to feed on the host the temperature sensitive eggs begin to hatch. The larvae then enter the host through the insect bite or even along a hair follicle. Some can even just burrow into the skin and they remain inside the host growing and developing until they are mature.

Once they have spent 5 to 10 weeks maturing they then work to the surface and drop to the ground where they molt and develop into an adult fly and repeat the process.

In Brazil the species that infects cattle has been responsible for millions of dollars damage to their milk and leather industries. The problem has been widespread for many years in South America but the Bot flies are now moving farther north. As temperatures increase so does their range. The orange area on the map shows their range as of 2002. Now they have been reported in Belize and Yucatan Mexico. Not just the cattle and rodent Bot flies but also the Human Bot fly.

I finally came to accept the Africanized (so called Killer Bees) bees got here and took over our hives and ruined our honey production in this country. I have made détente with the dreaded iguanas here in Florida but I am not ready to have alien possession of my subcutaneous tissues become a way of life. Check out the video below of the guy getting the larvae removed from his elbow following his Belize vacation.

Okay my Global Warming denying friends, don’t say we didn’t ask you to pay attention

http://www.youtube.com/watch?v=knQGq5V_cUs