Monday, September 19, 2011

Shigellosis


This week at Infection Landscapes, I will discuss shigellosis. This is a serious diarrheal disease that accounts for some of the greatest morbidity and mortality of all the diarrheal diseases we will consider. Its greatest burden is experienced by young children in the developing world. Shigellosis poses a pandemic threat, and in fact has caused a widespread pandemic within only the last 40 years.


The Pathogen. Shigellosis is caused by one of four pathogenic species of the genus Shigella. The species are classified according to serogroups and so the species are often referred to as serogroups. Shigella dysenteriae, S. flexneriS. boydii, and S. Sonnei are the four species that can cause disease in humans, which correspond to the serogroups A, B, C, and D, respectively. Here is the general morphology of the Shigella genus:


The bacteria are gram-negative bacilli and are non-motile. They are able to resist the low pH environment of the stomach, pass through and target the epithelial cells of the colon for infection. Unlike V. cholerae in the small intestine, Shigella spp. actually invade the epithelial cells of the lower intestine, which is facilitated by a lipoprotein antigen in the cell wall of the bacterium and the production of the Shiga toxin. The organisms invade and multiply in the epithelial cells producing ulcers in the epithelium of the colon and subsequent dysentery, for which shigellosis is known. Disseminated Shigella infection is quite rare as the organisms typically remain localized and do not cause bacteremia. Tissue damage in the colon is most pronounced in infections with S. dysenteriae. The mechanism by which the organisms invade the epithelial cells is quite interesting and indirect. Here is a graph published in Nature Reviews Immunology depicting the pathway of infection (Nature Reviews Immunology 4953-964 (December 2004)):



The Shigella bacteria cannot invade the epithelial cells of the large intestine directly. Rather, they are taken up by microfold cells (M-cells) and delivered to macrophages. The bacteria are able to lyse the phagosome by which it was taken up in the macrophage. Following apoptosis of the macrophage, the Shigella survive and can now invade the epithelial cell by way way of the Type III secretion system, which acts as a syringe for the infecting bacteria. The bacteria then infect neighboring epithelial cells by way of paracytophagy.

Antibiotic resistance is a serious problem with shigellosis and, in particular, with the type 1 strains of S. dysenteriae. These organisms were highly susceptible to many antibiotics during the 1940s, but after extensive use many are no longer effective. This has presented a substantial public health problem in dealing with epidemics of shigellosis in many parts of the world.

The Disease. Shigellosis is a diarrheal disease characterized by dysentery, that is, loose stool with blood and mucous. High fever and severe abdominal cramps are also common clinical features. This kind of dysentery is not unique to shigellosis, however, making the diagnosis on clinical presentation very difficult in the absence of laboratory or epidemiologic findings. Some other common causes of such dysentery are infections with Salmonella enteritidis, enteroinvasive and enterohemorrhagic Escherichia coli strains, and Campylobacter jejuni, which are all bacteria, and Entamoeba hystolytica, which is a parasite. While shigellosis is a dysentery diarrhea, watery diarrhea can still be present especially during the early stages of disease.

Most shigellosis cases resolve within a week, especially with effective antibiotic therapy. However, infections with S. dysenteriae type 1 can progress to a complicated clinical course. Their are two categories of complications. The first is intestinal and can include intestinal perforation, hemorrhage, rectal prolapse, paralytic ileus, and enteropathy with associated protein malabsorption. The second category is extraintestinal and can include hemolytic uremic syndrome, meningitis, vaginitis, arthritis, rash, hypoglycemia, and high white blood cell count. Such complications are serious and warrant immediate medical attention. The case-fatality for infection with S. dysenteriae type 1 can be between 10% and 20%

An example of rectal prolapse

If watery diarrhea is present during a Shigella infection, then the standard oral rehydration therapy should be employed. Packets of oral rehydration salts containing sodium chloride, potassium chloride, citrate and glucose can be obtained from almost any pharmacist or chemist in most areas of the world. These are simply mixed with water and consumed by the diarrhea-afflicted person. In addition, antibiotic therapy is often warranted in severe cases of shigellosis. But due to the high level of antibiotic resistance of the Shigella organisms, assigning the appropriate therapy regimen is complex and very much region specific. The local Shigella strains prevalent in a given geographic area in combination with the epidemiologic characteristics of endemic, epidemic, or sporadic cases must be thoroughly considered by those clinicians with the appropriate experience in treating shigellosis locally. This kind of laboratory- and epidemiology-based clinical decision making is critical to simultaneously prevent morbidity and mortality among the human population (especially young children) and to prevent increased antibiotic resistance among the microbial population. 

The Epidemiology and the Landscape. Both sporadic and epidemic occurrence of shigellosis is common. The bacteria can be both waterborne and foodborne, but direct person-to-person fecal-oral transmission is a very important mode of transmission, unlike what we saw for cholera. Humans are the only substantive reservoir, although apes can also be infected. The Shigella bacteria are highly infectious, requiring only a few score organisms to infect in most cases. As such, the person-to-person transmission capacity is greatly enhanced and, thus, this mode of transmission is much more important for shigellosis. Nevertheless, as with most gut infections that constitute a major global burden of disease, conditions of poverty and a lack of sanitation infrastructure delineate those geographic regions that suffer a disproportionate amount of the burden. It's just that the other player in the sanitation/hygiene partnership plays a much bigger role in the transmission of shigellosis because of its extremely high infectivity.

There are no good estimates of the country-specific geographic distribution of shigellosis. However, the global burden of disease is quite significant. between 120 and 165 millions incident cases are believed to occur each year. Furthermore, approximately 1 millions deaths occur annually, with greater than 60% of these experienced by children under 5 years of age.

The distribution of Shigella species varies geographically. In the developing world, under conditions of poor sanitation and overcrowding, S. flexneri is most prevelent, whereas in the developed world S. sonnei is the most common. In the United States, S. sonnei accounts for about 2/3 of shigellosis infections and S. flexneri about 1/3 of infections.

Control and Prevention. Control and prevention of shigellosis begins by following the usual guidelines: improving sanitation in resource poor areas and maintaining vigilance in personal hygiene. The latter is especially important in stopping the secondary transmission of shigellosis at the level of the household, which is a critical modality for this diarrheal disease.

Because of the high infectivity, potentially high case-fatality, and antibiotic resistance, epidemics of type 1 S. dysenteriae require more advanced control measures than the standard generic prevention strategies of providing safe drinking water and maintaining personal hygiene. Outbreaks involving this strain of S. dysenteriae require the identification of the source of each infection. Specific source tracking and elimination add a great deal of labor to shigellosis outbreak investigation, but thorough epidemiologic field investigation can substantially reduce the overall impact of an outbreak.

28 comments:

  1. I just wonder what percentage of incident cases are transmitted via water, food, or person to person. And after the source of the outbreak is identified, how easy is it to avoid the source? Such a disease seems like it would spread so quickly that it would be nearly impossible to control an outbreak.
    It seems as though, even though person-person transmission is responsible for the most number cases, the bacteria come from somewhere and that "somewhere" is probably unclean water. Is it truly that difficult to ensure that every person has access to clean water? The UDHR has added access to clean water to it's list of human rights, why isn't more being done?

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  2. The identification of the source must be difficulty to pinpoint. You have a disease with high infectivity, high case fatality rate, high yearly incidence which is both waterborne and foodborne.
    Shigella, along with the many other neglected tropical diseases, arise in resource poor countries, which as Dr. Walsh said can be treated with ORT. Salt and sugar may be readily available but the treatment itself is not taught to indigent populations. There is a recipe for a simple ORT, but most people do not know of it. It can probably save thousands of lives if that information was disseminated.
    The idea of Antibiotic therapy brings up another issue. In terms of health systems, access to health care services in places of poverty makes this treatment option difficult to obtain.

    Has shigella been seen in the U.S in recent history?

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    1. This is one of the biggest issues we face: the areas stricken by diseases like Shigella don't have the proper tools or resources to help combat it for a variety of reasons. Many 3rd world countries just don't have the manpower to combat something like Shigella because the population in these countries fall victim to other diseases that are much more prevalent in poverty stricken nations.
      Indigenous populations where education of any kind is scarce would allow the disease to run its course because they don't have the means or methods to stop it.

      Another curious thing that I wondered was what roles healthcare professionals in developing nations play when a person comes in with Shigella or similar diseases that thrive in poor countries. Would they themselves have the knowledge to combat the disease? Or would they relegate a patient to a bed only to try and temper the symptoms they see.

      According to the CDC, there are about 14,000 cases of Shigella in the US. Though the number of infections may be 20x greater because many cases aren't diagnosed or reported. Children the ages 2-2 are most likely to get Shigella and its far more prevalent in the summer than the winter. (http://www.cdc.gov/shigella/general-information.html)

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    2. When I saw Sayed's numbers from the CDC, they seemed low to me. Shigella is a bacteria that is on the "short list" when we evaluate a child with persistent diarrhea. As of the 10/15 CDC website posting, it is reported that every year, there are actually about 500,000 cases of shigellosis in the United States. The rate of infection is 4.82 cases per 100,000 individuals. This is not a small number at all. Just to clarify as well, the CDC reports that Shigellosis does not have a marked seasonality to its transmission. (http://www.cdc.gov/shigella/fast-facts.html)
      I think that an important feature of this bacterium is that, unlike cholera, antibiotics do play an important role in the recovery of the individual. As resistance to traditional first-line drugs such as ampicillin and trimethoprim-sulfamethoxazole is common, alternatives include drugs like ciprofloxacin and azithromycin to treat infections. As children under 5 seem to be the most vulnerable in the population, representing 60% of the million deaths that occur annually, there is a further limitation; the use of the antibiotic cipro is usually avoided in children, safe use of Cipro has not been established in the pediatric population. Another complication to treatment, as mentioned in this post, is that regional antibiotic susceptibilities must be reviewed when treating Shigellosis.

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  3. Shigella can survive for only a short period of time outside the human body. To check for the bacteria in stool, samples have be analyzed fairly quickly. Since speed is a factor in Shigella isolation and the disease has a high case-fatality rate, I wonder what the efficacy of surveillance must be during outbreaks?

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  4. There are many different kinds of bacteria that can cause diarrhea, so identifying the Shigella pathogenic species that cause Shigellosis can help determine the appropriate course of action. We know that Shigella is highly contagious and is passed from person to person by fecal-oral route. The problem lies in that some individuals experience mild or no symptoms of Shigellosis, but may still pass the bacteria on to others. It is interesting that most people with Shigellosis can recover on their own with an intake of fluids to prevent dehydration, yet they can be contagious for up to four weeks after diarrhea stops. Although promoting basic hygiene and hand-washing is very important in the developing world, it is hard to do so when clean water and soap may not be available. Also, workers picking fruits and vegetables can impact the spread of Shigellosis if the produce is contaminated. Access to care and antibiotics may be limited to the developing world, however, a global intervention should be devised to prevent this infectious disease from spreading. In cases where Shigellosis is not treated and severely affects individuals, are there any long-term consequences to an individual’s health?

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    1. Similar to the responses below, it was interesting the see the dynamic effects that this infection can have on the body. Complications of shigellosis include reactive arthritis which causes painful swelling of the joints and eye irritation. These symptoms can last for months or years. Other complications manifest more quickly and have more dire consequences including bloodstream infections, seizures and hemolytic uremic syndrome (HUS) which causes kidney failure, seizure, stroke coma and death. In rare cases (but more common in the S. dysenteriae infection subgroup), there can also be a deadly complication called “toxic megacolon.” This rare complication takes place when the colon becomes paralyzed, preventing bowel movements or passing gas. Symptoms and signs of this infection include abdominal pain and swelling, fever, weakness, and disorientation. If left untreated, the colon may rupture and cause peritonitis, a life-threatening condition requiring emergency surgery.

      Reference:
      http://www.foodborneillness.com/shigella_food_poisoning/

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  5. When I hear person to person fecal-oral transmission, with 120-160 million infections annually and 1 million deaths mostly in children under 5, I realize the importance of hand washing and effective sanitation and infrastructure. This means the poorest countries in the world would be at the most disadvantage. Shigellosis is also highly infectious, with only a few organisms required to cause infection. What can we do to minimize this rate of infection and reduce the case fatality rate? S. dysenteriae type 1 has a 10-20% case fatality rate. Not to mention the high resistance to antibiotics, what can truly be done? Is education about hand hygiene and adequate sanitation and infrastructure enough? Advanced control and prevention measures such as specific source tracking and elimination will help, but is this enough for shigellosis?

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  6. Improving sanitation, ensuring safe drinking water and maintaining personal hygiene - they all are the familiar prevention strategies for many fecal-oral diseases. While these prevention strategies should be emphasized, they often require resources and infrastructure that developing countries cannot afford. However, vaccines hold great promise - examples include the small pox eradication and near eradication of polio - and further development needs to be encouraged. The University of Maryland is working towards development of the Shigella flexneri (the most common Shigella serogroup in the developing world). The vaccine is all ready in Phase 2 trail and hopefully results will be promising.

    http://www.ord.umaryland.edu/AUTM09BWR_UMaryland.pdf

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  7. You mention the high disease burden of Shigellosis. Where does it fall in regard to other intestinal diseases both in the US and in the rest of the world?
    The greatest burden is felt by children in the developing world. Children are less likely to know how to properly wash their hands. Training kids in proper hygiene techniques could go a long way in lowering the disease burden from this disease.

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  8. Christopher DonnellySeptember 23, 2011 at 4:34 PM

    Shigellosis, like many diseases that have been fought with antibiotics, has started to exhibit antibiotic resistance, especially with the type 1 strains of S. dysentariae. With the growth of antibiotic resistance, how have the number of cases, or severity of cases grown in recent history? How have public health and research efforts grown to address this issue? The severity that can be caused in cases with the type 1 strain is a big concern, especially in areas where shigellosis is a major issue.

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  9. Elizabeth Jennifer LeeSeptember 23, 2011 at 5:33 PM

    I think it's interesting that children account for most cases of shigellosis, partly due to inadequate toilet training and lack of basic hygiene. Many diseases can be prevented simply by being more clean and careful, granted there are adequate resources available to do so.

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  10. Response to Waqas:
    There is a hope in the GH communited that vaccine development can reduce the burden that diseases like Shigella cause. If Shigella, which is the cause of most bloody diarrhea and dysentery worldwide, can be prevented with a vaccine a lot of deaths can be prevented.

    I also think a simple, universal prevention/mitigation strategy is surveillance. Improving surveillance mechanisms in resource poor, densely populated areas can surely help control widespread outbreak of the disease.

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  11. Response to Chris:
    That is an interesting point to make, being that Shigellosis is indeed starting to exhibit antibiotic resistance. I wonder what is being done about this issue and also what is being done for those people who do not have access to antibiotics whatsoever. What outreach efforts exist for resource-poor areas and what course of action is proposed to help outbreaks of Shigella?

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  12. Response to Bobbin:
    Your points are interesting and I also wonder about the detection of outbreaks, considering the necessary sample of fresh, bloody stool. It would be interesting if a Shigellosis outbreak was covered in our class text. I wonder what the investigation process would consist of.

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  13. Response to Andriane:
    A majority of the cases of Shigellosis resolve completely with appropriate hydration and electrolyte therapy, as well as antibiotic therapy in the most severe susceptible cases. There is, however, a small number of cases (appx. 3% of Shigella Flexneri cases) that progress to Reiter's Syndrome in genetically predisposed individuals, which involves irritation of the eyes, painful urination, and pain in the joints. Further sequelae include hemolytic uremic syndrome and rheumatoid arthritis. http://www.textbookofbacteriology.net/Shigella.html

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  14. response to George:

    http://www.cdc.gov/ncidod/dbmd/phlisdata/shigtab/2006/ShigellaAnnualSummary2006.pdf

    This is the latest summary I could find on the CDC website of laboratory confirmed shigella isolates in the US in 2006. There were about 10,000 isolates, 72% were S. sonnei and only 0.5% were S. dysenteriae. 1/3 of cases affected children under 5.

    Evidently, there are at least 10,000 confirmed cases every year, so one can only imagine that the true incidence is probably much higher.

    That rectal prolapse photo is very unsettling.

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  15. To add to what Stella said, symptoms of reactive arthritis such as Reiter's Syndrome also include heel pain, swollen toes/fingers, pain/burning during urination, mouth ulcers, and skin rashes. Reiter's syndrome mostly affects men between 20 and 40 years and individuals who have the human leukocyte antigen B27 seem to have a genetic predisposition to the disease. http://www.mayoclinic.com/health/reactive-arthritis/DS00486

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  16. In response to Andriane Melanthiou:

    Shigella infection can causes several rare complications such as rectal prolapse, toxic megacolon, instestinal obstruction, colonic perforation, bacteremia, hypovolemia, hyponatremia, leukemoid reaction, neurologic symptoms (seizures, encephalopathy, coma) reactive arthritis and hemolytc-remic syndrome. The most common of these are hypovolemia, hyponatremia and neurologic symptoms (seizures).

    Source: http://www.uptodate.com.newproxy.downstate.edu/contents/clinical-manifestations-and-diagnosis-of-shigella-infection

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  17. I thought that the way in which the Shigella bacteria infect the intestinal epithelium indirectly through the M cells was very interesting. M cells are found throughout the intestine, including the small intestine, especially the ileum. However, this article explains that the shigellosis infection is very localized to the colon. I was very curious what distinguishes the M cells in the large intestine from those in the small intestine such that only the colon epithelium is susceptible to infection in this case.

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  18. Response to Jennifer, Dov and others:
    In these comments, the observation is frequently made that children represent a disproportionate burden of disease and that improved hygiene such as hand washing is key to prevention. While I agree that this makes a lot of sense logically, I wonder how practical this suggestion really is. I wonder whether children really have poor hand hygiene due to lack of education/training, or if children are simply too young to have the concentration and focus to practice good hygiene. As well, it seems to me like putting everything in their mouths is just an inherent behavior among children. I am skeptical that the behavior of children can really be changed in a significant or substantial way.

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  19. This article continues the theme of disease striking at poverty-stricken locations. High infectivity was mentioned in the article, so I did some research on what that meant. Apparently an inoculum as low as 10 to 100 bacterium can cause shigellosis (1)! That level of infectivity is terrifying, and has implications for water filtration and sewage disposal in resource-poor areas (they would need better treatment plans). Since direct contact and food and water transmission are possible, this high infectivity also raises the possibility of a pandemic, given the current speed of international travel.

    The article also mentioned that antibiotic treatment varied across regions because the organism has become resistant in different pockets of the world. Supportive care is relatively easy to provide with standard oral rehydration therapy, but even getting antibiotics would be difficult in certain areas, and getting second-line drugs after first line drugs had failed would probably be even harder. These same areas are likely to also be affected with poor hygiene standards (possibly due to lack of water to wash hands often as is instructed) and a lack of safe drinking water, compounding the issue of control of the causative organism.

    (1) http://www.uptodate.com/contents/shigella-infection-epidemiology-microbiology-and-pathogenesis

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  20. The post talks about the high antibiotic resistance of shigella, and I just wonder whether there is enough training for medical students and current physicians to understand the issue. Some physicians may not recognize the importance of this issue because their focus is individual care; as long as they can treat their patients, they may not care about the consequences of the overuse of antibiotics. I am not surprised by the fact that poverty and lack of sanitation play an important role in the transmission of shigellosis, as they do for many other enteric diseases. Unfortunately, this is associated with the amount of resources that a country has, and it is difficult to prevent such disease when the basic health infrastructure is incomplete. I just wonder if the burden of shigellosis has been about the same for a long time, or if there has been improvement in some regions. I am also curious about why the strain of S. dysenteriae has higher infectivity. Would it be related to the virulence factors on this species?

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  21. Something this post mentioned that I think is very interesting and important about Shigella spp. is antibiotic resistance. Prior to the resistance that came about between 1940 and 1960, first-line treatment was amoxicillin. According to Harrison's Principles of Internal Medicine, recommended treatment is now ciprofloxacin, a fluoroquinolone (a category of drug to which resistance has emerged as well). It seems to me that inappropriate antibiotic treatment by physicians probably has something to do with this, although I wonder about patient education as well: could some of this resistance be due to patients not taking the full course of their prescribed antibiotics? If this is the case (in fact, even if it is not the case for Shigella), what is the best way to increase awareness of the public health impact that individuals may have in their choosing to not complete a course of such drugs? This behavior increases the risk of drug resistance, but I know of very little literature related to public education.

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    1. After reading Ben's comment, it made me think about all of the other illnesses that have elaborate regimens. Even though amoxicillin is a normal treatment for many things, having a difficult treatment regimen makes it hard for patients to be compliant. However, if patient education is lacking, even if the regimen is simplistic, patients might not know the right questions to ask and/or not understand the severity of their health issue. Going hand-in-hand with patient education is physician education. If providers do not understand the correct dosage and treatments, it can cause issues. Especially if a patient ever sense their provider does not know/understand what they are doing, why should they follow their advice?

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  22. 1- Health education plays a huge role in controlling and preventing this diarrheal disease especially in underdeveloped countries. In developed countries such as the US, health care providers have quick access to laboratory tests to identify Shigella in the stools of an infection person, and also to determine whether or not antibiotics are needed to treat the infection. However, in undeveloped countries, such resources are limited and health professionals may not be able to quickly rule out other diarrheal diseases. This could be part of the reason, out of so many, why there’s an increased antibiotic resistance in the strain populations.

    2- Interestingly, according to the CDC, 2% of those infected with Shigella Flexneria can develop post-infectious arthritis which can lasts for months or years. Also, there were reported cases of children experiencing seizures while infected with shigella. The mechanisms through which both of these complications occur is unknown. This can be a new research development to further explore in the nearest future.

    3- Close monitoring of children in daycares, schools, playgrounds, swimming pools and places of children congregation is much needed.

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  23. The global burden of the disease is rather significant and highly transmittable through consuming contaminated food and beverages prepared by persons with inadequate personal hygiene when handling food, consuming foods that have been contaminated, and drinking from contaminated water. Although, Shigella Flexneria is more prevalent in the developing word and here in the United States it is Shigella Sonnei is more common, I wonder how prevalent the more fatal and infective species of type 1. Shigella Dysenteria is and what other control measures can be taken to prevent it beyond good sanitation and personal hygiene practices. Additionally, I wonder how long it takes for the onset of symptoms to start in order to track the source of transmission more easily.

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  24. After researching shigellosis vaccines, I found that there are ongoing efforts to create and disseminate effective vaccines against particular prevalent serotypes of shigellosis (http://cid.oxfordjournals.org/content/early/2014/07/16/cid.ciu471). I wonder that if some of these vaccines do prove effective and reduce morbidity and mortality of certain serotypyes of shigellosis, would the other serotypes become more prevalent in areas previously unaffected by these serotypes?

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