Economic Impact of Dengue Illness in the Americas: $2.1 billion

Shepard, D. S. , et al.  Economic Impact of Dengue Illness in the Americas. (2011). Am. J. Trop. Med. Hyg. 84 (2): 200-207. http://www.ajtmh.org/cgi/reprint/84/2/200.

This paper looks at the economic burden of the Dengue virus in the Americas.  Dengue is mosquito born and has been emerging in countries previously considered free of disease.  Increasing development, international travel, and urbanization have contributed to this upward trend in disase.  From 1950-1970, the Americas were considered to be esentially dengue-free because of eradication of its host, Aedes aegypti.  However, waste managemnet problems and uncontrolled urbanization led to the revival of dengue into America.

This paper reports the five major components they used in measuring the burden of disase on society:
1) the number of reported dengue cases
2) the degree of underreporting
3) the direct and indirect costs per case
4) the DALY burden per case
5) the country's demographic information

As you might guess, these data are not completely straight forward.  This is why they performed a sensitivity analysis and determined that the range for the economic burden was in the range of $1-4 billion.

Dengue Surveillance and underreporting: To determine the rate at which dengue is underrepoted, the researchers found five field studies that estimate the underreporting rate.

Dengue costs per case: To figure out this number, the authors consudcted a systematic literature review in PubMD and found cost data was limited.  For quality reasons, they decided on the results of two cost studies: a large sutyd in 2005 for 5 countries (Brael, El Salvador, Guatemala, Panama, and Venezuela) and one sutdy in Puerto Rice.  The studies documentsd direct medical, direct non-medical, and indirect costs of dengue cases.

After being adjusted for underreporting, they found there was 5.6 million cases, with Brazil having the highest contribution.  This contributed to a total of $2.1 billion lost in direct and indirect costs.

This paper demonstrates the methodology many researchers use in order to perform cost analysis for the burden of a viral illness.  It demonstrates that often these calculations ar enot straight forward and authors must create ways to get around limiting data such as underreporting cases.

--Lauren Platt

Source: Shepard, D. S. , et al.  Economic Impact of Dengue Illness in the Americas. (2011). Am. J. Trop. Med. Hyg. 84 (2): 200-207. http://www.ajtmh.org/cgi/reprint/84/2/200.

Researchers turn Salmonella into an Anti-viral Gene Therapy Agent

Researchers at Cal’s school of public health have successfully genetically modified the Salmonella bacterium in order to use it for the treatment of viral infections, such as cytomegalovirus.  This anti-viral treatment/ technique utilizes the salmonella bacterium as a “safe transport vehicle for virus-stopping enzymes.” Specifically, salmonella acts as a vector for delivering RNAse P ribozyme to infected cells.  Ribonuclease P rybozyme is a unique enzyme that “targets the overlapping mRNA region of M80.5 and protease, two murine cytomegalovirus (MCMV) proteins essential for viral replication.”

The treatment operates upon the fact that Salmonella evolved as bacteria capable of surviving the human digestive system. Salmonella was a particularly appealing vehicle for the anti-viral treatment as the food-borne pathogen- turned gene therapy agent because it could be swallowed (providing a much easier means of administration than vaccine injections). Furthermore, Salmonella could be attenuated to create a strain of bacteria with low cytotoxicity and pathogenicity.

Researchers Liu and Lu tested the capacity of Salmonella to bring viral rybozymes into the human cell. They experiments were first carried out in cell cultures, then tested in vivo in murine models. The strains of bacteria were also mutated and tested to ensure that they would not cause sickness in the mice.  When the CMV infected mice were administered the bacteria containing the ribozyme plasmid it became evident that the active form of the bacteria at least doubled the life of the CMV infected mice.

Bacteria seem extremely useful as anti-viral gene-therapy. They can deliver necessary genes and enzymes to host cell populations, and can be grown with relative ease low cost in cell cultures. Who knows, this technique could also be used to treat many other viral infections. 

http://www.pnas.org/content/early/2011/02/03/1014975108.full.pdf+html

http://insciences.org/article.php?article_id=9855

http://www.pnas.org/content/early/2011/02/03/1014975108.abstract

Alysha

Researchers turn Salmonella into an Anti-viral Gene Therapy Agent

Researchers at Cal’s school of public health have successfully genetically modified the Salmonella bacterium in order to use it for the treatment of viral infections, such as cytomegalovirus.  This anti-viral treatment/ technique utilizes the salmonella bacterium as a “safe transport vehicle for virus-stopping enzymes.” Specifically, salmonella acts as a vector for delivering RNAse P ribozyme to infected cells.  Ribonuclease P rybozyme is a unique enzyme that “targets the overlapping mRNA region of M80.5 and protease, two murine cytomegalovirus (MCMV) proteins essential for viral replication.”

The treatment operates upon the fact that Salmonella evolved as bacteria capable of surviving the human digestive system. Salmonella was a particularly appealing vehicle for the anti-viral treatment as the food-borne pathogen- turned gene therapy agent because it could be swallowed (providing a much easier means of administration than vaccine injections). Furthermore, Salmonella could be attenuated to create a strain of bacteria with low cytotoxicity and pathogenicity.

Researchers Liu and Lu tested the capacity of Salmonella to bring viral rybozymes into the human cell. They experiments were first carried out in cell cultures, then tested in vivo in murine models. The strains of bacteria were also mutated and tested to ensure that they would not cause sickness in the mice.  When the CMV infected mice were administered the bacteria containing the ribozyme plasmid it became evident that the active form of the bacteria at least doubled the life of the CMV infected mice.

Bacteria seem extremely useful as anti-viral gene-therapy. They can deliver necessary genes and enzymes to host cell populations, and can be grown with relative ease low cost in cell cultures. Who knows, this technique could also be used to treat many other viral infections. 


Sources: 


http://www.pnas.org/content/early/2011/02/03/1014975108.abstract
http://insciences.org/article.php?article_id=9855


Alysha

Dengue Vaccine

The National Institute of Allergy and Infectious Diseases suggests that finding a vaccine to control dengue fever is promising.  There are several possible candidates that are currently being tested at various levels.  Specifically, there is a chimeric vaccine that is being developed by Sanofi Pasteur that should be available by 2015.  This is actually the leading contender for possible vaccines.

As many as 50 million people a year are infected with dengue fever.  Usual dengue fever control is focused  on transmission reduction, such as eliminating still water that serves as breeding grounds.

The pan American Health Organization in San Juan, Puerto Rico increased spending on dengue from $5 million in 2000 to $30 million in 2005 and $44.4 million last year, with 68% to basic research, 24% to vaccine, 12% to treatments, and 2% to diagnostics.  Additionally, the Australia’s George Instititue for International health reported that the world spending on dengue in 2008 was approximately $126.8 million.

http://www.medpagetoday.com/InfectiousDisease/GeneralInfectiousDisease/24937#rate

http://globalhealth.kff.org/Daily-Reports/2011/February/18/GH-021811-Dengue.aspx

Diana

Using Monoclonal Antibodies to Treat Chikungunya

Two new fully human monoclonal antibodies have been discovered which could battle Chikungunya, a disease that currently has no available vaccine or specific treatment (Togaviridae). They were developed by culturing immune cells isolated from an individual who had developed resistance to Chikungunya.


This shows a practical, modern application of the monoclonal antibody technique we were discussing earlier, developed from sendai virus (paramyxo). 


full article: http://www.sciencedaily.com/releases/2011/02/110216111935.htm


-Catalina Angel

Clinical Trials: Using Reoviruses to Treat Cancer

Reoviruses are successfully being used in clinical trials to treat patients with cancer. Not only does the virus cause cancer cells to die, it also forces them to release pro-inflammatory chemokines and cytokines, which in turn causes the patient's immune system to attack the disease. New research published by BioMed Central's open access journal Molecular Cancer shows that reovirus infected cancer cells secrete proteins which, even when isolated, result in the death of cancer cells.

Normal human cells are protected from reovirus infection by a protein called PKR. However a cellular signalling protein (Ras), which can block PKR activity, is abnormally activated in many types of cancer and provides a window of opportunity for reovirus infection. A multi-centre study, involving labs in the UK and America, collected growth media from reovirus infected melanoma cells. The researchers showed that this media contained a range of small pro-inflammatory proteins, including an interleukin (IL-8) and Type 1 Interferon (INF-β), which recruited and activated white blood cells, specifically Natural Killer (NK) cells, dendritic cells (DC) and anti melanoma cytotoxic T cells (CTL).

Since we were talking about the use of using herpes preference for rapidly multiplying (such as cancer) cells and then treating with acyclovir in class, I thought this would be a useful sidebar on the effects of another virus on cancer cells.


source: http://www.medicalnewstoday.com/articles/217129.php


-Catalina Angel

(VZV) Entrapment

In this impressively thorough paper from our own backyard, Stanford researchers from Ann Arvin's lab have provided evidence of a newly identified antiviral mechanism that can specifically "entrap"  VZV capsid protein in mature and immature forms in protein "cages." 

                                     Something like that.... only for VZV.

                                                                 

Protomyelocytic leukemia protein (PML) serves as the key structural component of PML-nuclear bodies (PML-NB), which have numerous morphologies and functions in mammalian nuclei. As this group reports, when PML-NBs form into spherical cages in VZV-infected cells, it is possible to observe sequestration of the VZV capsid protein ORF23, as well as immature/mature capsids.

They were able to use extremely high sensitivity cryoimmuno-electron microscopy (cryoimmuno-EM) to determine precisely whether the capsid protein was hed within the PML-NBs both in in vitro cultured cells and in vivo in human Dorsal Rot Ganglia and skin xenographs from  a severe combined immunodeficiency (SCID) mouse model.  They went on to determine that only one of the six PML isoforms, PML IV, possesses this antiviral capacity. As a final accent, they even found that these same PML-NBs were also responsible for sequestering the mutant aggregated protein Huntingtin, the cause of Huntington's disease. Thus, they conclude that PML can function to block viral assembly as well as contain potentially harmful protein aggregates.

- Vy Tran

Reichelt M, Wang L, Sommer M, Perrino J, Nour AM, et al. (2011) Entrapment of Viral Capsids in Nuclear PML Cages Is an Intrinsic Antiviral Host Defense against Varicella-Zoster Virus. PLoS Pathog 7(2): e1001266. doi:10.1371/journal.ppat.1001266

Measles everywhere!

A quick update about measles outbreaks around the world:

Another measles infected person who flew halfway across the world is causing a lot of trouble because of the possibility of infecting susceptible populations.

A woman flew in from the UK to New Mexico, passing through Dulles International Airport, Denver International Airport, and Albuquerque International Airport last week. Just another reason why we should stop global travel... or eradicate measles using the vaccine! This is so frustrating - why can't people just get vaccinated!!!!

http://www.medicalnewstoday.com/articles/217615.php

Yu-Jin

Efficacy of Vero-cell-culture derived influenza vaccines

In a double-blind phase 3 clinical trial, a vero-cell-cultured-derived trivalent influenza vaccine was found to provide a similar level of protection as the egg-based influenza vaccines currently in use. During the 08-09 flu season, half were assigned to receive the vaccine in trial and the other half were assigned to receive the placebo among 7250 participants. They found the efficacy of the vaccine to be about 78.5% and found no serious side effects from the vaccine. To test the efficacy, the analysis was based on intention to treat.

If this vaccine further proves to be as efficacious as the egg-based vaccine, this will give an edge to humans in the war against the influenza virus. Because the egg-based vaccine takes about 6 months to prepare, scientists have to make predictions as early as possible. Since the strain for the next year's flu epidemic tends to surface at the end of the current year's flu season, scientists base their predictions on this latest strain. However, waiting until the end of the epidemic is not a feasible option because the vaccines need to be in production earlier. Therefore, if the cell-culture derived vaccine, which will be manufactured more efficiently and quickly, is proven to provide similar levels of protection as the egg-based vaccine, we can make more reliable predictions regarding the new strain that will surface in next year's epidemic.

http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)62228-3/abstract

Yu-Jin

Whole-body "Scale" Analysis of a Viral Infection

From the Pasteur Institute in Paris,  Marion Ludwig and collegues report the first whole-body analysis of a viral infection in a vertebrate. Using zebrafish larvae, they were able to observe host-pathogen interactions due to the immediate advantages of being both  small and transparent. Zebrafish have long been a well-established model organism as they are generally small, breed readily, externally fertizable with fast developing embryos, ease of genetic manipulation and high homology with human genes and cell types. As this paper describes, microbiologists are now taking a "pike"-ing to using this fish model .

Researchers experimentally infected the larvae with heat-adapted Infectious Hematopoietic Necrosis Virus (IHNV),  a Rhabdovirus that causes severe disease and hemorrhaging in salmonid fish (trout, salmon, et al.).  They were then able to follow the course and patterns of infection in the entire animal through the use of whole-mount  in situ  hybridization (WISH) and whole-mount immunohistochemistry (WIHC). They found that the primary target of the virus was vascular endothelial cells with the most severe damage in blood vessels. They were able to utilize the virus's temperature sensitivity to examine critical time points of infection. By shifting to the non-permissive temperature at numerous time points post-infection, they determined that if the virus was not inhibited or cleared 12-15 hours post-infection,  pathology would emerge. Unfortunately for the fish, this is too short of a period for the host immune system to respond accordingly.

Though there are dolphinately some set backs to this system (including that there are no known natural viruses of zebrafish) these researchers believe that this can prove to be a valuable tool in the future and most certainly has a plaice in studying viruses. 

- Vy Tran

Ludwig M, Palha N, Torhy C, Briolat V, Colucci-Guyon E, et al. (2011) Whole-Body Analysis of a Viral Infection: Vascular Endothelium is a Primary Target of Infectious Hematopoietic Necrosis Virus in Zebrafish Larvae. PLoS Pathog 7(2): e1001269. doi:10.1371/journal.ppat.1001269

(I'm sorry for all the marine puns. I'm ofishally stopping now.)

Measles outbreak in Switzerland

Despite the recommendation of childhood MMR vaccination in Switzerland, an outbreak in Geneva has occurred, targeting mainly adults and almost exclusively affecting individuals of inadequate immunization. Geneva and its surrounding French border region are unusually susceptible to contagious diseases such as measles because of the continual movement of international visitors and existence of cultural groups that discourage routine vaccination. In turn, Switzerland is a frequent source of measles import to the United States. 

This report follows one published by ProMED in 2009 concerning an outbreak in Switzerland that had only reached 50 cases by February, in contrast to this year’s count exceeding 2000 cases. Swiss health officials are emphasizing continued vaccination on the recommended schedule (2 vaccinations, at 12 months and at 15-24 months) and isolation of infected and exposed persons at home.

Nina 

ProMED Mail 

Identifying the “must-have” genes for microbes

B. thetaiotaomicron

Science has reported on the development of a new mol bio technique called insertion sequencing, which involves using transposons (mobile DNA fragments) to introduce mutations in to populations of bacteria. This development has allowed for in depth investigation of microbial genomes. The transposons are tagged so that mutant strains may be tracked in varying environments or growth media. The researchers responsible for insertion sequencing (Junjie Qin and colleagues at BGI Shenzhen) first applied the technique to B. thetaiotaomicron, a human gut bacterium, and introduced the WT and mutant strains to mice in order to determine competitive advantage of certain mutations.  Decreases in abundance of mutant strains in the mouse gut indicated that the mutated gene was essential to growth in the gut. This work is of note because it follows from research published by David Relman of the ID department here at Stanford (see Science 10 June 2005, p. 1635) and also because it speaks to the efficiency of microbial genomes, something exemplified by viruses. 

Nina

E.P. Digging deep into the microbiome. Science. (2001). 331:1008-9.

Images of Viruses: Russel Kightley Science Images

Hey all,

I just found an awesome website with some great viruse graphics I thought I'd show you in case you were interested.  The guy does tons of cool science imagery, and he does an entire section of viruses.

http://kightleys.photoshelter.com/gallery/Viruses/G0000O8RZEbjxjmU/

I really urge you to go to the website for inspiration on your model.  The images are copyrighted, or else I would paste a sneak peak here.   Check it out.

Lauren

A Novel Human Polyomavirus Closely Related to the African Green Monkey-Derived Lymphotrophic Polyomavirus

A study was just published in the Journal of Virology about a potential zoonoses in the Polyoma family.  There are currently 8 human polyomaviruses (JCV, BKC, Merkel Cell) but they don't generally get much attention in infectious disease media due to the fact that they don't tend to cause significant disease.  As I was reading the article, I  was reminded of the Herpes family quite frequently as many of the polyomavirus infections  can infect people in a persistent manner throughout life and tend to only become apparent in immunocomprimised individuals by causing serious symptoms.  In fact, as the burden from polyomaviruses in immunocomprimised individuals becomes more prevalent, they are more often referred to as emerging opportunistic infections.

A result of the lack of concern about polyomaviruses in the past has led some researchers to the conclusion that there are probably many more human polyomaviruses circulating in populations that we are unaware of.  In order to test this hypothesis, the authors of the study tested samples (blood, CSF, and feces) from almost 600 patients (many of them suffered from immunodeficiency, often as a result of AIDS) to see the prevalence of polyomavirus infections within this specific high risk group.  The most interesting result of their study was the amplification of a previously unknown PyV sequence from a kidney transplant patient.  After comparison of the genetic sequence with other members of the Polyoma family, they came to the conclusion that the sequence is actually most similar to a PyV of African green monkeys, known as lymphotrophic polyomavirus (LPV).  The researchers have labelled this possible zoonoses as HPyV9.  Evidence of HPyV9 was also detected in more of the original samples, however much work needs to be done to find out about the replication process, persistence, and pathology of this newly discovered virus.

http://jvi.asm.org/cgi/reprint/JVI.02602-10v1?view=long&pmid=21307194

-Katie

OPV-related poliovirus (dedicated to Yu-Jin)

As we've talked about in class, poliovirus infections have been nearly eliminated due to the eradication efforts of various public health organizations, dedicated individuals, and massive funding. The four remaining regions: Nigeria, Afghanistan, Pakistan, and India, are especially difficult countries in which to eradicate polio due to issues of poverty, lack of infrastructure, and civil unrest.

Myanmar, which was declared polio-free in the year 2000, saw it's first non-imported polio case in years last December. A 7-month-girl who had not been vaccinated became an isolated case infected with a poliovirus believed to originate from the live-attenuated Oral Polio Vaccine (OPV). Because OPV strains replicate in the gut after vaccination, mutation of the strain may lead to shedding of infectious virus into the environment via human excrement. Conditions of poverty, such as poor hygiene and sanitation, facilitate the transmission of poliovirus from feces to human being. ProMed released a report today noting that Myanmar, which immunized over ten thousand children in response to this polio case, is continuing to vaccinate against poliovirus.

The report does not talk specifically about the type of vaccination given in Myanmar, but it would be interesting to see whether they chose to use OPV or the inactivated vaccine. It seems that since polio was eradicated and the infant girl was the only one affected, using inactivated vaccine would be ideal, especially since the young girl was infected by an OPV-mutant strain. Mass vaccination with OPV could potentially lead to more of these mutant-strain infections.  It is interesting to consider what the country has access to and whether mass vaccination with IPV would be feasible with regards to the resources and skills required to administer the inactivated vaccine.

-Autumn

Use of virus-mimicking particles to induce life-long immunity to Yellow Fever

 At the Emory Vaccine Center, scientists have found that virus-mimicking nanoparticles may play a crucial role in the development and maintenance of future vaccines. The scientists mimicked the Yellow Fever vaccine, a live-attenuated vaccine that activates the immune system by stimulating Toll-like receptors (TLRs), by designing nanoparticles similar to the Yellow Fever virus with regards to size and composition of immunological components. The particles were "studded with molecules that turn on Toll-like receptors". When used in mice, the virus-like particles induced life-long immunity to Yellow Fever, just as the live-attenuated Yellow Fever vaccine does.

Implications of these findings suggest that these synthesized nanoparticles may be used in vaccines to induce immunity to an infection when material for vaccines is in low supply, as is common in the case in pandemics or emerging infections. Moreover, these nanoparticles may play a role in developing vaccines to induce immunity against widespread and/or dangerous infections that do not yet have vaccines.

http://www.sciencedaily.com/releases/2011/02/110223133846.htm

-Autumn

Condoms at Carnival

A short blurb in the Washington Post states that Brazilian health authorities have launched a campaign encouraging people to use condoms if they engage in sex during the Carnival celebrations. The main reason for this campaign is to prevent the spread of HIV/AIDS. The campaign is intended for everyone, but especially targets young females. One of the television advertisements that is being broadcasted shows a young female telling her friends that they should carry condoms since Carnival is approaching. Otherwise, they shouldn't have sex.

This article reminded me of how social and cultural activities can greatly facilitate the transmission of a disease. Bringing large numbers of people into one geographical region for an event frequented by casual sexual activity can greatly increase the spread of a virus like HIV, even if the virus is not easily transmitted compared to viruses that transmit via respiratory routes.

Link: http://www.washingtonpost.com/wp-dyn/content/article/2011/02/25/AR2011022503709.html


-Autumn

Antiviral activity found in abalone

Marine antiviral drug discovery is a promising scientific venue because of viral abundance (about 10⁹ per liter) in oceans and subsequent evolution of novel compounds exhibiting antiviral activity. The high rate of viral infections in marine environments has driven natural selection, supporting the evolution of innate antiviral mechanisms and compounds in marine organisms.  These compounds include secondary metabolites, bioreactive peptides, and proteins. Recognizable antivirals that have been adapted from a marine organism include acyclovir and AZT, which were synthetically modified from arabinosyl nucleosides isolated from a sea sponge.

This particular study examined a commercially harvested gastropod, Haliotidae, which has been suffering epidemic viral ganglioneuritis, caused by a herpes virus (AbHV). Antiviral activity of Haliotis laevigata against HSV-1 was suggested by the research. Plaque assays revealed that lipophilic extract from digestive glands have greatest effect when added an hour after infection, while haemolymph worked best when added soon after infection. This suggests that there are at least two antiviral compounds in abalone, at least one that operates early in infection, and one later in infection, during an intracellular stage. The next step will be to quantify and isolate these reactive compounds and explore their respective mechanisms of activity.

Dang et al. In vitro antiviral activity against herpes simplex virus in the abalone Haliotis laevigata. Journal of General Virology. 2011. 92(3):627-37.

Distribution of HIV-1 and HSV-2 epidemics in Chad

A recent study was done in Chad exploring the possibility that Herpes Simplex Virus 2 (HSV-2) is a significant co-factor for the transmission of HIV-1 in different regions of the country.  The researchers took blood samples from adults in most of the regions of the country (2 regions were inaccessible at the time of the study) and did serology tests on dried blood samples.  Each sample that was randomly selected for serology testing was tested for HIV-1 and HSV-2.  The number of samples chosen for testing from each region was proportional to the population in the region, so as to acquire meaningful geographic disease rates.
The results from HIV-1 were fairly constant throughout the country while there were hot spots with high rates of HSV-2.  Two of these hot spots included areas that harbor many displaced individuals from civil conflicts that are a known high-risk group for HSV-2 and other STIs.  The data does not prove that HSV-2 is a significant biological co-factor for HIV-1, however the article suggests that transmission of the two diseases, that together make a devastating diagnosis, is inherently linked and hot spots, such as those discovered in southern Chad, are in serious need of health intervention.

http://www.ncbi.nlm.nih.gov/pubmed/21330743
-Katie

Increased Risk of herpes Zoster among patients with chronic obstructive pulmonary disease

 A recent study publication suggests patients with COPD are at an increased risk of herpes zoster in relation to the greater population, with the most significant risk for patients with COPD and currently using oral steroids. 

The study was done because COPD is commonly associated with systemic inflammation and irregular immune function, that was expected to predispose patients to developing herpes zoster.  Thus the study was executed with data from the Taiwan Longitudinal Health Insurance Database. 

The study incorporated 8486 patients with COPD and 33, 944 control patients, and suggest that those with COPD are more likely to develop herpes zoster.

I suppose it was already commonly known that weakened immune systems will be more prone to herpes zoster, but does it really make a difference to relate the disease occurrence with COPD.  It is interesting, but I don't think the who cares factor is big enough for this study to be influential in the health care setting.  I don't think it will change treatment significantly, except for suggesting the vaccine be delivered to differing populations.  Either way, I do not think the disease is serious enough to lead to any significant change because of this study.

http://www.cmaj.ca/cgi/content/abstract/cmaj.101137v1

http://news.health.com/2011/02/22/copd-may-make-shingles-more-likely/

Diana