Wednesday, June 6, 2012

Schistosomiasis


This week we begin to explore a new phylum, the Platyhelminths, or flatworms. This phylum contains two major classes of parasitic worms, the cestodes (Cestoda) and the trematodes (Trematoda). These animals are physiologically much simpler than the nematodes, as they do not have a digestive tract or a circulatory system. In this ongoing series, we first cover the trematodes (blood flukes and liver flukes) and then we will cover the cestodes (tapeworms). Schistosomiasis, which we are going to cover this week, is responsible for a substantive burden of disease across large areas of Africa, Asia, and South America.

The Worm. Schistosomiasis, also known as bilharzia, is caused by trematodes of the genus Schistosoma, also commonly referred to as blood flukes. There are three main species that cause human infection, Schistosoma mansoni, S. haematobium, and S. japonicum. S mekongi and S. intercalatum also infect humans, but are of lesser importance. There are also several additional species that infect other animals, most often livestock. In this discussion we will focus on the three primary schistosome species that cause most human infections.

S. mansoni male-female pair

The life cycle of these three (as well as the other two species that infect humans) follow the same general developmental stages. Schistosoma ova are expelled in the definitive host feces for all three schistosome species, and in the urine for S. haematobium and S. japonicum. In fresh water, these eggs will hatch and release the miracidia, which are motile in water. Subsequently, these miracidia seek out the intermediate host, which is one of several species of freshwater snail depending on the specific environment, geographic location, and schistosome species. The miracidia penetrate the foot of the snail and develop into sporocysts, which then produce daughter sporocysts that make their way to the snail's hepatopancreas. In the hepatopancreas these second generation sporocysts develop into cercariae, which is the larval stage that is infective to humans. The cercariae have evolved several remarkable strategies to find and infect their definitive hosts. Anatomically, the cercariae are equipped with a long forked tail that provides for prodigious swimming capacity after they exit the snail. The cercariae migrate out of the snail according to a diurnal pattern that follows light cues. The cercariae swim upward, following wave vibrations, chemical trails, and obstructed light patterns in the water, all of which can indicate the presence of their human (or other mammal) host. Upon finding a host, the cercariae penetrate the skin, lose their tail, and transform into schistosomulae, which migrate through the skin seeking out capillary beds and venules. Once they gain the venous circulation, the schistosomulae are transported to the lungs, where they develop further, and then move on to the liver, where, in the sinusoids, males and females pair off. The helminths feed on red blood cells in the sinusoids. Among mating pairs the female is enclosed in the gynaecophoric channel of the male:


After pairing these male-female schistosome pairs remove from the liver to the mesenteric veins where they will mate for life. The schistosomes require approximately 2 months to become fully mature, which marks the point when females begin to release eggs. These eggs, when mature, are able to pass through the endothelium of the veins and the epithelium of the intestine (or bladder) where they pass out of the host in the feces (or urine). The graphic below by the Centers for Disease Control and Prevention (CDC) nicely depicts the general life cycle of schistosomes:

The Snail. Freshwater snails are the intermediate hosts of schistosomes. There are four main genera of these freshwater gastropods that are capable of serving as the intermediate hosts for schistosomes. Biomphalaria are the intermediate hosts for S. mansoni:

Biomphalaria snail

These snails are aquatic but air-breathing. They prefer slow moving or stagnant surface water systems and are distributed in tropical areas in South America and Africa. Bulinus snails are the intermediate hosts for S. haematobium:

Bulinus snail

These snails are aquatic, air-breathing, and also prefer stagnant or slow moving water systems. These snails are distributed throughout Africa and the Middle East. Oncomelania snails are the intermediate hosts for S. japonicum:

Oncomelania snail

These snails are aquatic, breathe with gills and prefer fast moving, lotic water systems. They are distributed throughout east and southeast Asia.

The Disease. The clinical spectrum of schistosomiasis is extraordinarily complex and encompasses both acute and chronic disease, which differ by schistosome species. Most low volume acute infections are asymptomatic, and will not present with either acute or chronic disease. However, high volume acute infections, especially in naive hosts, will frequently manifest acute clinical disease. A syndrome consisting of some combination of cough, fever, malaise, hyper-eosinophilia, lymphadenopathy, and hepatosplenomegaly appear anywhere between 2 to 12 weeks following exposure to infectious cercariae.This syndrome is known as Katayama fever (after a valley in Japan, from which early descriptions of the disease were reported). This acute syndrome likely results from the migration of the schistosomulae through multiple organ tissues (see life cycle above).


Chronic infection and subsequent disease is responsible for the great global burden attributable to schistosomiasis. Chronic disease is primarily due to years of the deposition of eggs by reproductively active females in the tissues of the host. As females release their eggs, only approximately 50% make their way into the lumen of the intestine (in S. mansoni and S. japonicum infections) or urinary tract (in S. haematobium) and exit the host. The remaining eggs stay embedded in host tissues. Chronic symptoms are associated with both the expunged and embedded eggs and manifest according to Schistosoma species.

Schistosoma mansoni and Schistosoma japonicum:

The paired adults of these species are located in the mesenteric veins, where females release their eggs into the lumen.


About half of these will make their way into the lumen of the intestine and are expunged from the host. The breach of intestinal epithelium by the the eggs results in bleeding into the intestinal space leading to blood in the stool and diarrhea, which are common symptoms in chronic infections. In high volume chronic infections, intestinal blood loss can be substantive and lead to anemia. The consequences of "hidden" schistosomiasis in young children with heavy infections can be particularly severe with impaired physical and cognitive development.

The approximately 50% of schistosome eggs that are not expunged stay embedded in the intestinal epithelium or liver parenchyma. These embedded eggs stimulate potent inflammatory responses in the host and lead to granulomas and fibrotic lesions.


Portal fibrosis leads to hepatomegaly and splenomegaly. Subsequent obstruction of the portal circulation can lead to both portal hypertension and esophageal varices, which in turn can manifest in the transport of schistosome eggs to the lungs and hematemesis, respectively. The re-deposition of eggs in the lungs can also stimulate inflammation locally, resulting in pulmonary granulomas and pulmonary heart disease.

Chronic high volume S. japonicum infections seem to present greater risk for liver cirrhosis and hepatic cancer, as well as colon cancer, because this species produces up to 10 times more eggs than S. mansoni, which subsequently lead to a far greater number of granulomas.

Schistosoma haematobium:

The paired adults of this species are located in the venous plexus of the bladder. As with the other Schistosoma species, only about 50% of the eggs are successfully expunged from the host. These eggs are released into the vasculature, where they penetrate the endothelium of the blood vessel and then the wall of the bladder. In these infections, the breach of the bladder wall by the emerging eggs leads to hematuria, polyuria and dysuria.

Again, approximately 50% of the schistosome eggs are not expunged and remain embedded in the wall of the bladder.


As with the other Schistosoma species, these embedded eggs are potent stimulators of inflammation, which leads to fibrotic lesions in the bladder and calcification:


In high volume chronic infections, urinary fibrosis can obstruct the urinary tract leading to urinary stasis and secondary bacterial infections.

Chronic high volume S. haematobium infections are also associated with a relatively high risk of squamous cell carcinoma of the bladder.

The Epidemiology and the Landscape. The are currently over 200 million people throughout the world infected with at least one species of Schistosoma helminth. There are 76 endemic countries, but the greatest burden (≥ 1 million infections) occurs in 30 African countries and Brazil. Approximately 20 to 50 million people experience substantive disability due to their infections. The map below, published in Acta Tropica (Volume 120, Supplement 1, September 2011, Pages S121–S137), depicts this global distribution including those areas where schistosomiasis has been eliminated:


The distribution of disability-adjusted life years associated with schistosomiasis reflects the distribution of endemicity:

Age-standardised disability-adjusted life year (DALY) rates from Schistosomiasis by country (per 100,000 inhabitants).
   no data
   less than 50
   50-75
   75-100
   100-150
   150-200
   200-250
   250-300
   300-350
   350-400
   400-450
   450-500
   more than 500

The distribution of schistosomiasis is primarily a function of the distribution of the intermediate host snails. The maps below, which were produced by the Schistosomiasis Research Group at Cambridge University, depict the geographic distribution of species-specific schistosomiasis:

Global distribution of S. mansoni infections  

Notice how the geography of schistosomiasis caused by S. mansoni conforms to the distribution of Biomphalaria snails described above.

Global distribution of S. haematobium infections

Notice, here, how the geography of schistosomiasis caused by S. haematobium conforms to the distribution of Bulinus snails described previously.

Global distribution of S. japonicum infections

Finally, notice how the geography of schistosomiasis caused by S. japonicum conforms to the distribution of Oncomelania snails described previously.

The landscape epidemiology of schistosomiasis is a confluence of the schistosome relationship with its preferred intermediate host, local snail habitat and water environment, and, finally, the human activity (occupational, domestic, and/or recreational) that creates contact points with this habitat. So, as with so many human infections, the disease ecology is really defined by the intersection of the physical landscape and the human social landscape.

Control and Prevention

Snail Control

Early (and some ongoing) attempts at schistosomiasis elimination focused on gastropod control in various surface water sources. Typically, these control campaigns have involved the chemical treatment of freshwater sources to eliminate the local snail population, thus blocking transmission of the schistosomes at the intermediate host. However, two important problems make gastropod control unrealistic in many settings. 

First, the chemical treatment of water sources can have much broader ecologic impact than what is intended by the public health initiative. Introducing toxic agents into surface water may kill the snails, but it can also harm other organisms in the aquatic ecosystem and result in unanticipated and detrimental ecologic effects. Some investigations have explored the possibility of introducing biologic mechanisms of control to supplant chemical treatment with more "natural" mechanisms. However, these approaches can also be dangerous if the natural biologic mechanisms involve the introduction of non-native invasive species into the aquatic environment. Nevertheless, the use of some plants in specific aquatic environments has been quite successful. For example, planting Sarcoca dodecandra, i.e. the gopo berry shrub, in water sources kills any snails present. 

Second, whether chemical or natural, snails in most areas prove robust to elimination. Both their high reproductive capacity and diffuse distribution within the aquatic system usually allow some members of the population to survive, which can then re-populate the local environment fairly quickly.

Deworming

The World Health Assembly has adopted deworming treatment with praziquantel as the primary approach to schistosomiasis control. According to the goals of the World Health Assembly and the Schistosomiasis Control Initiative, between 75% and 100% of school-age children in endemic areas should be treated with praziquantel. In highly endemic areas, large-scale, population-based, systematic therapeutic and prophylactic treatment of the population has proven far more effective than selective treatment of diagnosis-confirmed individuals.

De-worming campaigns do offer some hope for area-specific elimination, since there is a safe, effective, easily administered, and fairly cheap anti-helminthic drug available (i.e. praziquantel). However, as one might expect, there are obstacles to overcome in de-worming. First, praziquantel is not free and, while the price dropped by over 90% in the 1990s, without adequate funding poor communities will not be able to prioritize the cost, especially since many infections are generally asymptomatic. Second, effective ways to deliver the de-worming medications to communities need to be implemented, which can be logistically challenging particularly in remote communities or during times of the year when travel may be restricted (i.e. during the rainy season). Third, the extensive use, or misuse, of these drugs will likely lead to antihelminthic-resistance in the schistosomes, thus making the drugs ineffective. Nevertheless, if adequate resources can be put behind de-worming campaigns, and if delivery systems can be adapted to actively engage community members in the delivery and monitoring of these de-worming medications to simultaneously circumvent logistical obstacles and reduce the development of resistance, then substantial reductions in schistosomiasis may still be possible.


24 comments:

  1. This life cycle is so interesting.

    I read elsewhere that the WHO also recommends certain degrees of community wide praziquantel treatment based on percentage of children in the community with blood in their urine.
    -Less than 20%-> mass treatment is not implemented
    -20-50%->school age children are treated
    -greater than 50%->the entire community is recommended for treatment

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    1. That is an interesting recommendation by the WHO. It would mean doing urine tests on all children in all the schools of the endemic country. May be easily feasible in a smaller country, but what about a big one? Plus, limited financial resources and many other issues raised by some of us in the earlier posts could be major hindrances in implementing it.

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  2. Stephanie SaettaJune 20, 2012 at 1:32 PM

    The prevalence map made it seem that quite a few areas have had success in eliminating schistosomiasis, which is very encouraging. I am wondering which methods were used where, particularly for Southeast Asia. I know some endemic areas are currently using community health workers to reach rural populations for various other health issues, many of whom are trained in TB DOT. Considering their knowledge of drug resistance, influence, and accessibility, they would be a great resource for de-worming campaigns in highly endemic areas.

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    1. Russel Sharif (MPH)October 5, 2012 at 11:47 PM

      Hi Saetta,
      What I have learned is that Schistosomiasis is readily treated using a single oral dose of the drug praziquantel annually. As with other major parasitic diseases, there is ongoing and extensive research into developing a schistosomiasis vaccine that will prevent the parasite from completing its life cycle in humans.

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  3. I totally agree with Abhishek that available resources become a limiting factor when it comes to using some test for the mass treatment especially in developing countries. In addition, it will be an important thing to do a cost effectiveness analysis comparing Praziquantel along with urine test to giving the same medication to identified cases.

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  4. I think Jatinder has a great point on the significance of analyzing cost-effectiveness. Abhishek also raised the question about the significance of deworming campaigns in larger towns. Similarly, I wonder whether the cost effectiveness of long term deworming campaigns have been analyzed. Is there a signicant decrease in infection over a few years? Or will another deworming campaign have to take place in the same area a few years later.

    Caleb

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  5. The drug that is effective against this parasitic infection is praziquantel and the manner in which the drug is effective in killing the parasite is not well understood. Some say that the drug increases the permeability of the cells membrane for calcium which leads to paralysis and is then ejected by the immune system. Another theory is that the drug interferes with the amino-acid adenosine which is responsible for the transfer of ATP (energy) within the parasite. It appears that this drug is relatively cheap and effective and I am wondering why the WHO hasn't made a greater effort to curtail this disease especially within poor endemic areas.

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  6. I read a paleoepidemiology article that attempted to explain the disease history of schistosomiasis in ancient Egypt. Through analyzing fossilized snails, identifying the infection in mummified corpses, and looking through ancient “medical records” they were able to recognize the distribution of the disease throughout Egypt. They found that young men who engaged in agricultural work and were in constant contact with water were most likely to be exposed and contract schistosomiasis. Developing schistosomiasis, through the species S. haematobium, would often lead blood in the urine, which was so common that it was seen as “male menstruation” and a part of normal development. Most of the men who had schistosomiasis were young, pubescent and would develop the disease around the same time they joined the workforce. Without ever fully realizing the cause of the disease, it was understood that the irrigated bodies of water were likely to cause exposure but contact with the water could not be avoided due to its role in everyday life. Upon discovering that the disease is spread through schistosomes, effective public health measures (safe water practices, medication, etc.) have been taken to significantly reduce the number of infections in Egypt.

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    1. Hi Rukhsana,
      I read your comment and thought it is quite fascinating that I started retelling it to my friends since I am from Egypt and like to talk about fascinating historical events and stories that relates to medicine :)
      I also like to add another story/event regarding Schistosomiasis and it's management in Egypt, that around 1950 the Government did a large control campaigns using intravenous tartar emetic, the standard treatment for schistosomiasis at the time, as community-wide therapy. During this period that time syringe/needle sterilization techniques was not the same as today and the disposable needles were not available. "This commendable effort to control a major health problem unfortunately established a very large reservoir of hepatitis C virus (HCV) in the country so that by the 1990s, HCV had replaced schistosomiasis as the predominant cause of chronic liver disease" http://www.ncbi.nlm.nih.gov/pubmed/16628669
      So I wonder that what would we see years from now as a late consequence of the large scale use of praziquantel? and what other diseases that have some of these unique stories?

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  7. Thanks Rukhsana for the information and the history of schistosomiasis. It's interesting that people believed in "male menstruation" back then and that public health practices have made such a positive impact.

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    1. It is very intriguing that the schistosomiasis infection was considered male menstruation. Great advances and mass praziquantel implementation has lowered the incidence greatly. However, I recently had a patient who traveled to Dominican Republic, returned and was diagnosed with schistosomiasis infection. Surprising to find schistosomiasis infection is prevalent in DR.

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    2. Hi Dr. Rao,
      Very interesting that you saw such a patient. I was intrigued when I read your comment because I was familiar with Schistosomiasis in the Caribbean but did not know any details about it, and I found some really interesting information online. One thing, which may actually be worth your investigation, is that a 2011 article in Neglected Tropical Diseases mentions that schistosomiasis was thought to have been eliminated in DR almost ten years earlier (the article can be found at http://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0000964 under the heading "Schistosomiasis"). I haven't found any more current data, but if there is none you might be able to write this case up (if it is not too late now) as evidence that Schistosomiasis still exists in that country. I also found an article at http://www.sciencedirect.com/science/article/pii/S0001706X1200191X that compares prevalence data from 2003 and 2010 in various countries, including DR, which might also be interesting.

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  8. Sheaba Daniel

    Schistosomes have quite a fascinating and complex life cycle. It is good to know that the disease is preventable through drug treatment, health education and access to clean water. However, as mentioned, there are several barriers in developing regions to prevent/control Schistosomiasis.

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  9. Schistosomes are arguably the most clinically relevant and globally destructive trematodes Public Health physicians and investigators must target. Their ability to cause chronic infection can lead to squamos cell carcinoma of the bladder (S. haematobium) and portal hypertension (S. mansoni). Praziquantel has proven to be a successful anti-helminthic therapy; it's mechanism of action works via increasing the tegument permeability, thus resulting in a calcium influx leading to schistosome tetanus and paralysis. While there are de-worming campaigns suggesting the use of praziquantel as a means for prophylaxis, this is not a solution to preventing chronic disease from shistosomiasis because praziquantel does not behave like a vaccine. It is more like malaria prophylaxis and can prevent infection for a finite term until the next dosing. Elimination from a geographical region is no easier because snails are the intermediate host/reservoir, and is there such a chemical or even organism that can specifically target snails without directly or indirectly influencing other organisms in the snail's ecological niche?

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    1. I agree- It is unsettling knowing the severe ramifications of Schistosomiaisis as a chronic disease as well as an acute one. Additionally, elimination efforts will be quite difficult given the uniqueness of the snail as an intermediate host. I wonder if there is another drug out there other than Praziquantel that can be more effective and will help intervene in high risk areas earlier, prophylactically. Ironically, urbanization has limited the exposure.

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  10. Like most diseases with an animal vector or reservoir, control of infections presents such a major challenge. The problem with artificially altering an ecosystem is that it is not possible to predict all the consequences until they have already occurred. The article mentions that the use of some plants like the gopo berry shrub have been successful in killing snails, the intermediate host. If you can mitigate the effects of such a serious public health problem with a natural solution versus introducing toxic chemicals in to the water, it seems like the best course of action. But could there be ecological consequences to introducing plants that do not naturally occur in that particular ecosystem? I wonder if any of the local governments in these areas have given consideration to using the plants.

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    1. I agree. When someone messes with nature, we can never know the ramifications until it is too late. I think that schistosomiasis is and will continue to be a major public health burden as long as there are under-resourced, poor tropical countries. I therefore think that it is obviously important to regard schistosomiasis with the importance that it deserves. I think that a disease and pathogen like this requires multiple solutions that can be applied with maximum efficacy and efficiency, while reducing secondary harm at all costs. I wonder if there are computer models that have simulated what the effect of removing those snails from the ecosystem would be or of adding a foreign plant species. Unfortunately, models are models for reason, and as stated previously, we will never know the true outcome of messing with nature and the repercussions are already occurring.

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    2. What an interesting lifecycle Schistosomes have, the fact that they invade snails and then follow light patterns, wave vibrations and chemical trails to reach their definitive host is beyond fascinating to me. The measures of prevention and treatment for this complex endemic are multilevel as depict in the reading therefore I agree with Alexia in that it thus needs to be addressed with multiple solutions. Along with administering Praziquantel, additional control measures could be taken such as improved water and sanitation as well as reduction or elimination of intermediate host snails. A multilevel approach could sustain and/or enhance control of transmission.

      The use of chemically treated water to reduce or eliminate snails is out of the question for the obvious concerns that we have all raised. I do find an introduction of a foreign plant species an interesting and more sustainable approach; however, it still raises the concern about the potential impact on native species and plant life that play an important role in that ecosystem and economy. Here an invasive species can become a sustainable and economical food choice such as the blue catfish introduced in the Chesapeake Bay in the 70s. On that note I did read that the Gopo Berry Shrub not only was poison for snails but also a means of making soap and shampoo.

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  11. In addition to the disease burden on the GI tract, Schistosomiasis is a major contributor to bladder cancer which is the most common malignancy among young Egyptian males. Among older males, it's the second most common cancer (following liver cancer) and for females, its close third following breast cancer (liver still the leading cancer).

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    1. http://cebp.aacrjournals.org/content/21/3/537.full
      http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2763030/
      http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2150141/

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    2. Abraham, if it is such a public health burden with major secondary consequences, shouldn't the Egyptian, or any other government, make it a priority. Perhaps they have. One of the main issue could be the price of the drug (though significantly reduced in recent years), its availability in certain areas, does it require a cold chain, etc. There are a host of logistical issues with getting the drug to the area, not to mention the mechanism of action of the drug. Might it be easier to alter the intermediate host instead? I don't know, nor do I sanction snail genocide!

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  13. According to WHO and Global Network, more than half of all documented cases of schistosomiasis occur in Africa with Nigeria being the world's most endemic country for this disease. The Carter Center Control Schistosomiasis Program in Nigeria is an ongoing initiative that seeks to reduce the overall disease burden through treatment and health education. As a result of this programming, there has been drastic reductions in the rates of blood in schoolchildren's urine. A novel approach to CC is its incorporation of other treatment interventions, against diseases such lymphatic filariasis and river blindness, in conjunction with schistosomasis. This is definitely an innovative way to solving multiple health issues at once.

    In addition, a single annual dose of praziquantel is sufficient enough to control and treat Schistosomiasis, therefore, should there really be a concern for antihelminthic- resistance?

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