Wednesday, January 12, 2011

Dengue Part 1: The virus and the global burden of disease


We are going to discuss different aspects of dengue fever over the next couple weeks. This is the single most important arthropod-borne viral infection in the world, and may be second in importance only to malaria in terms of overall arthropod-borne infections. You may be thinking right now...what the heck is an arthropod, and what does this thing have to do with infections? Well, an arthropod is any organism that has an exoskeleton, a segmented body, and jointed legs. That means arthropods include many different organisms, such as insects, crabs, lobsters, spiders, and scorpions, just to name a very few. Of course, not all of these arthropods transmit dengue. When we talk about this particular arthropod-borne infection, the arthropods we are talking about specifically are the mosquitoes that act as vectors in transmitting dengue virus. In epidemiology, a vector is simply an animal (usually an arthropod) acting as a pathogen carrier that can transmit an infection from one host to another. So dengue virus has a mosquito vector, and it is called an arthropod-borne virus (or arbovirus) because the mosquito is an arthropod. There are other arthropod-borne infections, whose vectors are not mosquitoes, but are still arthropods. An example of this is Lyme disease, whose disease-causing organism (in this case a bacterium) is transmitted by a tick vector (ticks are not insects like the mosquito, but are still arthropods). We will cover Lyme disease in later weeks as we continue the series on arthropod-borne infections.

So...back to dengue fever. This week we are going to discuss the global burden of disease, and a little bit about the virus itself. Next week we will talk more about the landscape ecology of dengue as we explore the mosquitoes that transmit the virus, and the climate and habitats necessary for their survival. We will also talk about how the human impact on the environment affects human infection with dengue virus.

Dengue fever is typically a tropical and subtropical disease. The burden of this disease is largely concentrated along the lines of latitude of the Tropics of Cancer and Capricorn. If you look at this CDC map you can see that most cases of disease are concentrated equidistant from and along the equator between these two lines. Here is another representation published by the World Health Organization (WHO):


If you compare the above WHO map to the Centers for Disease Control and Prevention (CDC) map link above, you'll notice that while the risk of disease transmission extends along the equator between the tropical lines across the globe, the greatest number of cases of dengue fever are occurring in Latin America and South and Southeast Asia.

In order to describe the burden of disease accurately we need to describe the different forms this infection can take. The more common form is known as dengue fever and there are between 50 and 100 million cases per year across the globe. This disease is characterized by fever, headache, malaise, and often muscle and joint pain. Indeed, the joint pain can be so intense in some cases that the disease is also known as "break bone" fever because it can feel as though your bones are breaking. Another common symptom of dengue fever is a rash (maculopapular in type), which is typically localized. Minor bleeding (for example, the gums) may also sometimes occur in dengue fever, but pronounced bleeding is not common in this more minor form of infection.

Dengue fever is typically self-limiting and is not usually associated with severe complications. You may feel quite sick for awhile, but full recovery is the common course. In fact, many cases of this form of infection are completely asymptomatic. So someone can become infected with dengue virus and have no idea they are infected.

Dengue virus has another form, however, and this is far more devastating. Dengue hemorrhagic fever (DHF) is a much more serious disease and can kill. DHF is characterized by loss of fluid from the circulation and subsequent hemorrhage, often severe, and typically involves the eye, oral cavity, and the gastrointestinal tract, which can often demonstrate the most severe bleeding. The dysfunctional circulation and loss of fluid also leads to diminished blood supply to tissues (known as hypoperfusion) and can ultimately lead to organ failure and death.  The case fatality for DHF is between 5% and 15%. This means that of every 100 people who acquire DHF, between 5 and 15 people will die from it. This is a very large number when you consider that approximately 250,000 people get DHF each year. What makes this disease so incredibly poignant is the rate at which it is growing each year. Take a look at this WHO graph to see the phenomenal rate of growth of dengue infection over the past 50 years:


But, you may be asking, if only a quarter of a million people acquire the severe hemorrhagic form of dengue, and if only 5% to 15% of these will die from the disease, even though any deaths are unacceptable from a public health perspective, how does this disease constitute a major global health threat (and I contend that it does) when compared to infections like HIV, malaria and tuberculosis, which together kill tens of millions of people each year, not just tens of thousands as dengue does? Well, the answer I would give is down to three major factors: 1) the nature of the virus, 2) the explosive growth of dengue infection across the world in recent decades as depicted in the graph above, and 3) the expansion of the vector mosquito that transmits dengue virus. The explosion in global infections in recent decades has much to do with mosquito abundance and habitat, which we are going to cover next time. But the nature of the virus itself is also extremely important in the consideration of dengue as a disease of major public health importance. So let's take a closer look at this virus now.

Just in case you were wondering, here is a representation of what the virus looks like:


This virus belongs to the family of viruses known as the Flaviviridae. Flaviviruses include many other arthropod-born viruses, including, for example, West Nile virus, Japanese encephalitis virus, St. Louis encephalitis virus, and yellow fever virus. All of these Flaviviruses are also transmitted by mosquitoes, although not all by the same mosquitoes, and not all Flaviviruses that exist are mosquito-borne or even vector-borne.

Critical to the epidemiology of dengue fever and dengue hemorrhagic fever, the dengue virus is comprised of 4 distinct serotypes. These are uncreatively known as dengue 1, dengue 2, dengue 3, and dengue 4. At least they are easy to remember! Dengue infection severity is believed to come down to infection with multiple serotypes. It is thought to go something like this: an individual is infected with any one of the 4 dengue serotypes circulating in his/her specific geographic region. The distribution of these serotypes is distinctly different across different geographical landscapes, but inevitably there are multiple serotypes in circulation wherever dengue is endemic. So an individual gets their first infection with one of the serotypes. They may or may not have symptoms with acute disease. If they do demonstrate clinical disease, they typically present with the dengue fever form of the disease, which was described above as demonstrating fever, headache, malaise, and perhaps a rash and severe joint and muscle pain. But the individual will most frequently recover completely and resume a healthy existence. Or, they may not have any symptoms whatsoever, and thus never know when they were first infected with the dengue virus. This is how it typically goes with your first dengue serotype infection. And indeed you will be immune to infection with this serotype upon any further contact with it.

However, the infection with the first serotype has done something a little bit nasty. It has sensitized you, in a particular way, to detrimental effects from new infections with dengue serotypes that are different from the serotype that originally infected you. Even though your immune system effectively controlled and cleared the first dengue infection, you have become immunologically primed to over-react to subsequent infections with different dengue serotypes. The causes behind this are believed to stem from the following mechanisms. To begin, there are receptors on the cells lining blood vessels, known as endothelial cells, that become hypersensitized to dengue virus-associated antibodies that were produced during your first dengue infection. These antibodies bind to the dengue virus antigen of different serotypes, creating immune complexes that likely trigger an inflammatory cascade that can cause vascular damage and "leaking" of the micro-vasculature (i.e. the very small blood vessels). This leads to the bleeding and reduced perfusion common in DHF and dengue shock syndrome (DSS). It is important to note that we are at an early stage in understanding the mechanics of this disease. For example, there may be certain serotypes that are associated with greater risk of DHF upon secondary infection. For instance, dengue 2 infection following dengue 1 infection may be more important for DHF than dengue 4 infection following dengue 1. In addition, there is much to the specific molecular mechanisms involved in DHF and DSS that is unknown, so the above description is only meant to be a rough thumbnail sketch of the basic process that is currently believed to be involved in the pathway from multiple dengue serotype infection to more severe dengue disease. This is currently an extremely active area of ongoing research and there is much that remains unknown.

Incidentally, this unique character of more severe disease associated with primary and secondary infection with different dengue serotypes is precisely why vaccine development has been difficult for dengue. Any vaccine must provide immunity on two fronts. First, it must be protective against all 4 serotypes of the virus. Second, it must provide long-lived immunity. Failure of any vaccine to do both would likely put the recipient at increased risk for the more severe dengue hemorrhagic fever because it may serve to prime the host immune system for hypersensitivity to future exposure to dengue virus in much the same way that natural infection with one serotype increases the risk for DHF after exposure to another serotype. This is not to say that a safe effective vaccine is not possible. It is challenging, but there are candidates under investigation.

So, let's return to the burden of disease and summarize what we know about dengue so far and why this constitutes an important global public health threat. Given that there is an annual incidence of dengue fever of 50 to 100 million persons per year, AND given the dramatic increase in the rate of infection that has been steadily increasing since the 1950s, AND given that the severe form of dengue disease is associated with secondary infection with a different dengue serotype following the recovery of the first, AND given that the landscape of this disease is such that those who were at risk for their first infection are equally at risk for their second, there are currently billions of people at risk for contracting dengue hemorrhagic fever. It is simply a matter of time before the lives claimed by DHF expand on a global scale exactly according to how the less severe form of infection has expanded.

That is, unless we do something to change the landscape of infection.

Next time we will discuss the vector of the dengue virus, the mosquito of the genus Aedes, and the two species that are responsible for transmission, A. aegypti, the more important vector, and A. albopictus, the lesser but still significant vector. We will place the vector squarely in the context of landscape epidemiology and describe how landscapes of both mosquito habitat and human habitation are central to the spread and control of dengue fever.

We will also end with a discussion on the emergence of dengue fever in the United States, which is now underway.

27 comments:

  1. The burden of this disease is largely concentrated along the lines of latitude of the Tropics of Cancer and Capricorn.

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  2. Is a previous infection with dengue fever the only way the be susceptible to DHF? Also in the WHO graph on the rise of DF and DHF are the number of cases the sum of DF and DHF reports? Is there a proportional rise in DHF with a rise in DF?

    Thanks

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  3. What is the liklihood that those who get DF (either symptomatic or asymptomatic) will get DHF? Does it vary among the different regions (Latin America vs Southeast Asia)?

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  4. Are there other infections with a similar natural history involving the development of susceptability to anaphylaxis for which successful vaccines have been developed?

    -Becca

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  5. Does DHF include progression into the CNS and subsequent brain infection as do many of the other Falviviruses ? Also is it a concern that the actual cases of dengue are grossly underestimated since so many initial infections are asymptomatic ?

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  6. To respond to Jane, it would make sense that there would be at least a proportional rise in DHF. I would think, simply from a probabalistic view, that it would depend on how the map looks. If there is an increase in numbers of serotypes in various geographical areas, one would think that would increase the prevalence of DHF, since you are more likely to come across a second strain. This seems like quite a likely possibility, due to increased travel and globalization, combined with global warming perhaps making a more fertile ecology for the disease.

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  7. Claire,

    I read that there have been rare occasions that dengue viruses can cross the blood brain barrier and infect the CNS but it said that this was not common. In terms of your second question I have the same concern. I think that DF might be underestimated and also the prevalence of DHF might be misrepresented when prevalence data give the average of both DF and DHF cases reported.

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  8. CNS involvement is definitely not common and we simply don't have good numbers on the likelihood of DHF following DF because, as Jane points out, the primary infection with dengue virus is often asymptomatic or mild and so this is drastically under-reported. Thus, no reliable denominator. Robin makes a good point in that the more DENV variants present in a population the more likely you are to be exposed to secondary infections to new DENV types. I would add to this, however, that not only the presence of other types, but also their relative distributions matter. There is building evidence that secondary infections have a specificity to DENV variant in their pathogenicity for DHF.

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  9. Are there other infectious diseases where the original infection creates a hypersensitive, more severe response to subsequent infections from different serotypes?

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    1. In response to the previous post:
      One of the example is rheumatic fever which is an inflammatory disease that can develop as a complication of inadequately treated strep throat. Strep throat is caused by infection with group A streptococcus bacteria. The features of the disease are thought to be the result of a hypersensitivity reaction caused by cross-reacting antibodies. It is thought there is a combined humoral and cell-mediated immune response to the bacterium which, through molecular mimicry, cross-reacts with tissue in the heart, joints, skin and central nervous system. Cardiac involvement occurs in 30 to 70% of first attacks but subsequent attacks raise that figure to 75 to 90%. It is similar to Dengue that the subsequent attack of the disease causes a more serious damage to the human body after the first attack.

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  10. I would definitely have to agree with you about dengue fever being a major threat. It's scary that a subsequent serotype could be fatal. My uncle had the dengue fever and is perfectly healthy now but the info about the serotypes and the danger presented by it is disconcerting.

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  11. Thought this might interest you, its an article on NPR responding to the WHO press release on the increase in dengue cases worldwide, including within the United States.
    http://www.npr.org/blogs/health/2012/01/27/145987471/dengue-fever-cases-surge-worldwide

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  12. Without intervention, this seems to be a massive looming health crisis. Until a workable vaccine is available, prevention should be focused on improving water supply systems in endemic areas. More specifically, eliminating stagnant sources (even small ones) in places where people live and work will go a long way toward altering the landscape to interrupt the infection cycle. Community education to drain or cover potential breeding sites has a proven track record

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    1. Sheaba Daniel
      It’s interesting that India has the highest dengue fever burden in the world. India seems to have a yearly epidemic of dengue fever once the monsoon season begins, most likely due to all the water collected in puddles or potholes which act as potential breeding ground for the mosquitoes.
      Other preventative measures could be the spraying of insecticides, mosquito repellent, and teaching the population other measures such as to avoid leaving containers/trash near residential areas which could potentially collect water and act as a breeding ground.

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    2. Dengue fever is indeed an incredibly huge public health issue. I was born in Bangladesh, and I remember many relatives being infected with the dengue virus. Unfortunately one of my nieces is currently in the hospital being treated for a DF (actually I haven't asked if she was suffering from the more severe DHF). Mosquitos are an enormous problem in Bangladesh, for the same reasons Sheaba mentioned in her comment. Afterall India and Bangladesh are neighboring countries. It is pretty scary to think that being infected the second time is actually what causes a more severe reaction, because this adds to the complication of making a vaccine that can effectively combat dengue, especially since vaccinated individual's immune system may view the vaccine as a primary infection. However, I am hopeful we will be able to create an effective vaccine that will defend against all 4 serotypes for the entirety of a persons life.

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  13. The widespread implications of Dengue and Dengue fever is a public health problem that is not only growing and spreading and effects over 128 countries but there hasn’t been much successful efforts in stemming the flow. The complexity of making a vaccine that has to have immunity against all 4 different types of dengue viruses and produce also life-long immunity has eluded many scientists. Just recently though in April Sanofi has said that their vaccine for dengue fever has worked in the first stage clinical trial by reducing incidence of dengue fever by 56% in a trial that involved thousands of children in Indonesia, Malaysia, Philippines, Thailand and Vietnam. This Phase 3 trial compromised of 3 injections of the vaccine for 2/3 of the children and 1/3 received a placebo. However, there isn’t a peer-reviewed article on this yet since they are still analyzing their data and there isn’t much detail yet but would be presented in a medical conference later in the year. Although until that time, it does look promising and gives hope that this vaccine although not perfect is a step in the right direction.

    http://www.nytimes.com/2014/04/29/business/international/sanofi-says-dengue-vaccine-succeeds-in-late-stage-trial.html?_r=0

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  14. Dominican Republic was affected drastically by dengue and currently is being affected by chikungunya. Both diseases are similar and in fact are transmitted by the same mosquitos. In areas affected by this disease I think it is essential to educate the population of how the diseases are transmitted. Education is essential because a lot of rumors are recently being spread in Dominican Republic negating mosquitos as being the vectors. Also can both dengue and chikungunya be treated simultaneously?

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  15. The vaccine issue is really interesting, if the vaccine fails it can reinforce the host to be more susceptible to the the forms of Dengue. This shows the danger with Dengue due to the increased susceptibility if an individual was once infected with a type of Dengue.

    Looking at the graph, its interesting to see the drastic increase in rates of Dengue from 1955 to 2007. It looks like the rates of Dengue cases doubles per decade. And I’m curious to why. Is it due to higher demands for transpiration of goods from one country? or is there another underlying cause?

    If vaccines which have immunity for all 4 types is not created as of yet, then what type of interventions can possibly take place? What can be done to decrease the rate of Dengue if vaccines are not currently available?

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  16. Nicole MastrogiovanniJuly 24, 2014 at 3:33 PM

    I agree that is it very interesting how rates for Dengue nearly doubled per decade according to the graph shown. I think this increase could be due to climate change and the gradual rising temperatures creating better environments for mosquitos to adapt to. I also agree that it could be due to the increase of demand for products, especially tires, throughout the world making it easier for the mosquitos to spread elsewhere. For prevention methods we should definitely consider covering the stacks of tires that are main breeding environments and causing worldwide spread of Dengue as well as other open containers that are collecting rainwater and becoming perfect environments for mosquitos around communities and homes. Even though it is labor intensive to go around and spread awareness of covering open containers and monitoring it, it has been proven effective in the past and should be seriously considered to be an action we begin to take in order to decrease mosquito breeding and therefore prevent Dengue.

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    1. I completely agree with you Nicole. As we increase our use of motor vehicles so will increase our use of tires and so there may be increase spread of Dengue. It was labor intensive when the PAHO went to South America to decrease the amount of open water containers to decrease the spread of mosquitos in communities and homes, but with a 70% decrease of infection that followed how can anyone argue its necessity. One mosquito can lead to thousands more, these disease prevention methods need to be implemented as well as continued research for the vaccine.

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  17. I find it very interesting that certain serotypes that are associated with greater risk of DHF upon secondary infection like the example of dengue 2 infection following dengue 1 infection may be more important for DHF than dengue 4 infection following dengue 1. Hopefully there is a link between secondary infections following certain serotypes that can hint scientists in terms of preventing or strategizing worse types of infections, such as focusing on eradicating one serotype that is more harmful. Dengue is greatly on the rise as shown in the graph and does not seem to be getting the exposure in the news in deserves especially in the US where it is emerging as opposed to diseases of such rarity as Ebola.

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  18. It was really interesting to find out on Monday about the possibility of a new Dengue serotype. The 5th serotype was confirmed in the fall of 2013, although it was first detected in a viral sample taken from a 37 y/o farmer admitted to a hospital Malaysia in 2007. The discovery of serotype # 5 was especially groundbreaking considering the other 4 serotypes had been identified in the mid-20th century. The interesting part about the 5th serotype, or dengue 5 as I suppose it will be called if the nomenclature follows the previous 4, is that it's phylogenetically different from the other serotypes. The 5th serotype is transmitted among primates, as opposed to the other 4 which transmit among humans. Researchers suspect that the emergence of dengue-5 is likely due to genetic mutation or natural selection. From what I've read it does appear that the discovery of the new strain will delay vaccination development efforts.

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  19. http://nyti.ms/1LbBUY6

    The above link is for an article published last week about the current outbreak of Dengue fever in India which is considered the worst in decades. It's sad to read about the ill equipped hospitals and how desperate people are trying to find treatment.
    Although there are articles attributing the increased rate to global warming which contribute to longer warm season for mosquito growth, it's clear that this disease is on the up-swing and we will be hearing about those outbreaks more often in the coming years.

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    1. http://www.cnn.com/2015/11/11/health/hawaii-dengue-update/

      Hi Abraham, it looks like the outbreak in India is not the only outbreak of Dengue going on right now. The link is to an article about a Dengue outbreak closer to home: in Hawaii. The article reports that even though Dengue is not endemic to Hawaii, the virus was most likely "brought in" by an infected traveler who then subsequently infected a mosquito. So yes, the disease does seem to be on the up-swing in recent times.

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  20. It is interesting that the Dengue virus is made up of four different serotypes and that more than one serotype is in circulation when dengue is endemic. It is unfortunate that after infected with the first serotype people are sensitized to harmful effects from new infections. I am curious to know what is currently under investigating as a potential virus that is protective against all 4 serotypes of the virus in addition to providing long-lived immunity.

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    1. You probably mean a vaccine* (not virus ) that is protective. see next comment

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  21. Someone asked a good question in the lecture. What would happen if someone is infected by the four serotype all at one? We know that the major complications surrounding dengue is due to the sensitization of the immune system after fighting off the first serotype. Afterwards if the body detects a second serotype, the body will launch an over aggressive immunological response. Now what would happen if the person is infected with all four types at once? would the person become immune to all serotypes or perhaps the 4 serotype combined can have severe symptoms that are lethal.

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