Jenny Payne

HumBio 153: Parasites and Pestilence

February 28, 2010

 

Schistosomiasis Control: The need for a change in operations

Introduction

            Schistosomiasis infects 200 million people globally, causing morbidity in many more of those infected individuals than was originally suspected.  The effects of schistosomiasis can be chronic and detrimental to individuals and their families, and models suggest that the distribution of the schistosomiasis will grow considerably in coming years.  Thus, greater investment in the control of schistosomiasis is critical.  However, current control practices are focused on morbidity reduction rather than transmission interruption, and are unlikely to result in long-term sustainable suppression of schistosomiasis transmission.  Faced with this fact, it becomes imperative that more resources be invested in vaccine development, so that schistosomiasis may be more successfully controlled.

The forgotten burden of schistosomiasis

Out of the 200 million estimated schistosomiasis infections worldwide, 120 million are generally classified as asymptomatic.  However, emerging evidence suggests much fewer infections are actually asymptomatic and the number of chronic infections with critical but less acute symptoms is quite high.   Such damage is a caused by eggs that remain in host tissues and over the years cause fibrosis within various organs.  For S. haematobium, this organ is generally the bladder, whereas for S. japonicum and S. mansoni the affected organs are usually the intestine, spleen or liver.  This damage can cause a variety of conditions as it progresses, including cancer.

            Other forms of morbidity, such as anemia, are even less frequently acknowledged.  The link between anemia and schistosomiasis has been confirmed in multiple studies and persists even after adjusting for co-infections and diet.  Intensity of infection is negatively correlated with hemoglobin levels, although anemia has been shown in mild as well as moderate and severe infections. A study on S. japonicum found that anemia results from iron-sequestration prompted by cytokines.  Indeed, several studies found that resurgence of pro-inflammatory cytokine interleukins post-treatment was predictive of anemia associated with re-infection.  The involvement of cytokines implies that iron supplementation itself will not be sufficient to reverse anemia caused by schistosomiasis (King 2010). 

            Several recent studies have shown that even light infections can lead to growth stunting and undernutrition. Infection at a young age may also lead to impairment of cognitive development, which may or may not be reversible with treatment.  It is important to note that anemia, growth stunting and cognitive impairment are all associated with decreased economic productivity later in life.  Anemia has been associated with reduced work time. Stunting in adults due to childhood undernutrition may lead to decreased output from physical work and therefore reduced wage earnings.  A study in the Philippines found that an adult 15cm taller than average achieves a 13% increase in wage rate.  Stunting during childhood can also interfere with schooling, because children’s perceived readiness for school is often based on height.  Thus, the taller children enter school and therefore the workforce earlier.  Evidence suggests that a two-year delay in schooling may equate to a loss of 6% of individual lifetime wealth.  Thus, the impact of schistosomiasis extends far beyond the immediate symptoms (Guyatt 2000). 

            In addition, schistosomiasis infection can both increase susceptibility to and progression of co-morbid infections, including TB, HCV, and HIV-1.  Genital schistosomiasis may be much more common than previously thought and may increase susceptibility to co-morbid infections. In women, genital schistosomiasis causes ulcerations and lesions that may increase their risk of acquiring sexually transmitted infections, including HIV.   Beyond increasing susceptibility to new infections, schistosomiasis can also impact the progression of concurrent infections. Some studies suggest that chronic schistosomiasis accelerates HIV replication and immunosuppression, and consequently progression to active tuberculosis in individuals with all three diseases.  Similarly, the presence of schistosomes seems to enhance the progression to liver disease in HCV patients.  It is likely that other parasites, such as STHs, whose endemicity overlaps considerably with that of schistosomiasis, have some synergestic effect with schistosomiasis when an individual is co-infected, although more research on this relationship is needed (King 2008).

            Disability-adjusted life years are used to rank the burden of various diseases.  DALYs lost due to schistosomiasis are calculated with the view that the majority of infections are asymptomatic.  That is, anemia, stunted growth, undernutrition, and the effect on co-morbid infections are overlooked while calculating DALYs.  Whereas the previously accepted disability assigned to schistosomiasis was .5% disability, reassessments that take into consideration anemia, growth stunting, and other chronic effects calculate a disability weight ranging between 2 and 24% (King 2008; King 2005).  This translates to a 4-50-fold increase in the DALY burden.  Likely, the actual number is even higher given a lack of research on many of these chronic symptoms.  Understanding the severity of the effect of schistosomiasis is critical for attracting funding and developing appropriate control strategies. 

A picture of control and looming threats

            Progress in the control of schistosomiasis has been made in several countries in the last few decades, namely China, Japan, Brazil, Egypt, Morocco, Puerto Rico, Tunisia, Venezuela, the Caribbean Islands, Iran, Mauritius, and the Philippines.  Despite this, the number of infections and the number of individuals at risk has not changed over the last fifty years.  This is in part due to population growth, but the stability of this number also suggests that control efforts have had a minimal impact globally.  Where control efforts have been effective is often in areas where the number infected or at risk is relatively small.  Currently, 85% of infected individuals live in Africa, where very few control efforts have been sustained (Engels 2002). 

            The risk of schistosomiasis is likely only to grow in coming years. A study comparing models for temperature increase due to global warming with laboratory models of snail activity varying by temperature predicted that by 2050 8% of the total surface area of China will be at risk for schistosomiasis, which equates to additional 783,883 square kilometers from what is currently at risk (Zhou 2008). Increased temperatures may also have a substantial impact on cercarial output, especially for snails at lower latitude (Poulin 2003).  Thus, not only will the snail distribution be expanding, but snails in their current distribution will be release more cercaria.

            Economic initiatives involving agriculture or water also often have unintended consequences on schistosomiasis.  Construction of hydroelectric plants or irrigation canals, while beneficial for economic development, often have unintended consequences with respect to schistosomiasis distribution.  A change in the salinity and pH of the water created an hospitable environment for snails in an area that had previously had limited snail populations (Picquet 1996).  Similar scenarios have occurred in many other locations alongside water development projects, and fears abound regarding the impact of the Three Gorges Dam project in China on schistosomiasis distribution.  Given that water development projects such as this will likely become more common as development progresses, careful research about the potential impact on schistosomiasis needs to be conducted, and control measures must be in place.

Treatment-based control

Where control efforts are implemented, the first step is morbidity control.  This is primarily achieved through administration of praziquantel (PZQ), which is effectively the only drug used in treatment of schistosomiasis. A recent reduction in the drug’s price to ten centers per tablet has made it much more widely available for use.  Less than ten years after the construction of the Diama dam in the Senegal River Basin, there was a significant increase in both prevalence and intensity of urinary and intestinal schistosoma infections. 

PZQ administration is often focused on treating school-aged children, where it has been shown to be very effective in reducing chronic morbidity. Evidence suggests that the impact of treatment on morbidity decreases with age and that repeated treatment early in life has long-lasting effects through adulthood (Engels 2002).  Provision of treatment through the primary school system facilitates drug distribution among this age group.  In this process, a “dose pole” is used, which allows drug distributors to determine the appropriate dosage based on height, and circumvents the need for costly weighing equipment (Engels 2002). The effect of chemotherapy on improving growth, nutrition and anemia remains controversial.  It is possible that any improvement may follow a considerable delay not detected in many of the studies on this matter.  It is also possible that concurrent infections with malaria or intestinal helminthes cause enough damage that PZQ itself is not powerful to produce observable improvements (Richter 2003). 

            PZQ is effective against all five types of schistosomiasis, but to varying degrees.  Against S. mansoni, PZQ has been shown to reduce intensity of infection for up to 13 years after treatment. A single dose of PZQ does help reverse hepatic fibrosis caused by mansoni, but the reversal is delayed by 7 months after treatment in children and over 2.5 years after treatment in adults.  The effect is much more pronounced in children, and in areas of intense transmission in adults it is possible that no reversal may be seen at all (Richter 2003).  Effects are similar for S. japonicum and S. mekongi.  For S. haematobium and S. intercalatum reversal of urinary tract pathology is much more rapid than the reversal of hepatic fibrosis caused by mansoni.  However, resurgence of symptoms is also much more rapid.  Understanding the timing of this resurgence is critical for determining when to retreat patients.  Research so far has indicated that re-treatment less than a year after the initial treatment is not necessary.

Potential threats to treatment-based control

While praziquantel does have a remarkable impact on disease due to schistosomiasis and researchers have determined mechanisms of distribution and timing of administration to maximize these benefits, praziquantel still has several shortcomings.  Countering the successes of PZQ are the facts that reinfection often occurs promptly after treatment, even if these new infections are of reduced severity, and the cure rate is actually quite low.

The efficacy of the PZQ is determined by reduction in egg excretion rates, and the cure rate for the drug generally falls around 60%, sometimes as high as 85-90%.  Complete cure rates are seldom achieved.   One possible explanation for the low cure rate is that PZQ is not effective against young schistosomes.  The drug has been shown to be effective against schistosomes in early migrating larval stages, but susceptibility dramatically degreases around 3-4 weeks and is only regained once worms fully mature.  Treating patients who are at 3-4 weeks post infection will not contribute to a cure. 

The somewhat low cure rate makes the development of drug resistance a significant threat, and considering that PZQ is the only drug currently used in treatment campaigns, resistance would significantly hinder control efforts.  Whether or not there is currently resistance to PZQ is currently under debate, but several bits of evidence suggest it may already be occurring.  Even if it is not, the threat of resistance development in the future remains valid.  PZQ was used to treat infected individuals during an epidemic of schistosomiasis in Senegal, and cure rates were only 18-39%, which is far below the expected values.  Treatment with a second drug that is less frequently used yielded much higher cure rates, suggesting that these parasites had indeed developed some resistance to PZQ.  However, this evidence is not conclusive and it is possible that the low cure rate was a result of timing the treatment when much of the population still had young infections.  A similar situation occurred during an outbreak of S. mansoni in Egypt, and isolates of the schistosomiasis strain were grown in vitro and found to have much lower responsiveness to PZQ in vitro than other control strains. 

            Given the threat of drug resistance development against PZQ, other drugs against schistosomiasis may be needed.  Other drugs currently in existence include Oxamniquine, metrifonate and artemesinin.  Oxamniquine is effective against mansoni, and may be useful in regions where low cure rates have been found with PZQ against mansoni.  However, oxamniquine is not effective against haematobium or japonicum, and is relatively expensive, making it an unlikely choice of drug to be used in much of Africa.  It has been used extensively and successfully in Brazil and other South American countries, however.  Another drug,  metrofinate, was inexpensive, especially after a Kenyan company started producing it.  However, the drug is not as effective against haematobium as praziquantel is, and it must be administered in two doses, a disadvantage compared to the single required dose of praziquantel (Richter 2003).   Because of these disadvantages, production has been stopped. Artemisinin, derived from the plant Artemisia annua, has been found to be effective against immature worms, a trait not found in other PZQ or oxamniquine.  Because of this trait, it has been used prophylactically during major floods and has been effective.  However, artemisinin is also used against Plasmodium species, so where Plasmodium and schistosomiasis coexist, use of artemisinin against schistosomiasis may promote development of drug resistance in Plasmodium species.  For this reason it is not widely used in areas where the endemicity of the two parasites overlaps.  Other potential drugs against schistosomiasis have been studied, though research on most was abandoned once PZQ became available cheaply.  Most of these drugs are not strong candidates for use against schistosomiasis, with the exception of one that has been found to work in non-human primates.

Schistosomiasis control in the real world: A Chinese case study

            China is one of five countries heralded for its success in schistosomiasis control.  Beginning in the mid-1950s, China implemented a national control strategy that reduced the human prevalence of schistosomiasis by 90%.  Success has been attributed to early recognition of the public health and economic significance of schistosomiasis, commitment to a control strategy based on local resources, and strong political will.  Beginning in the 1950s, China deployed health education campaigns, which mobilized citizens to report the presence of the O. hupensis vector and the number of individuals in their communities with symptoms of schistosomiasis.  After collecting this data, teams surveyed the presence of vectors and disease throughout the countries and identified endemic regions.  From these initial surveys it was estimated that between 10.5 and 11.8 million individuals were infected at the time.  Structures were then established to operate a control program, which quickly began its activities.  Initialy, the control program consisted of free diagnosis and treatment along with numerous mechanisms of vector control and socioeconomic and educational interventions.  Snails were buried under thick layers of soil, sometimes after being treated with molluscicide, a strategy that proved highly effective.   Soil accumulated from newly dug irrigation ditches was used to fill old dishes, and dykes and fish ponds were constructed to alter the breeding habitats of the snails.  Thus, the initial campaign focused on transmission control, achieved by treating many patients, but also by focusing heavily on controlling snail populations.  This focus succeeded in reducing the area of snail-infested land by two-thirds. 

            With the development of praziquantel, efforts shifted considerably toward morbidity control.  In 1992, the World Bank Loan Project launched a control project with the goal of reducing the prevalence of human and bovine infection by 40% and reducing snail infection rates by 50%.  The primary mechanism of achieving this reduction was treatment with praziquantel, supplemented by education and snail control projects.  The WBLP project reached and in fact surpassed its goals, and proved highly effective at lowering schistosomiasis prevalence in 5 of the 12 provinces where it was once endemic.

            Unfortunately, recent surveillance data suggests that schistosomiasis prevalence has been increasing since the end of the WBLP 2001. (Utzinger 2001)  Several different surveillance systems have detected in ancrease in the number of cases and an expansion of snail-infested territories.  China has once again listed schistosomiasis as one of its top priorities, a move which will hopefully enable it to control what appears to be a reemerging epidemic (Utzinger 2001).  Similar reemergence following the cessation of chemotherapy campaigns wa also seen in the Lao People’s Democratic Republic and In Brazil.  In Brazil, chemotherapy reduced morbidity greatly, and in the Lao People’s Democratic Republic prevalence was decreased from 40% in 1989 to 1% in 1997 in response to repeated chemotherapy campaigns.  Both countries have since seen an increase in prevalence following the end of their chemotherapy campaigns (Xianyi 2005).

This recent lesson from China’s control experience, reinforced by data from Laos and Brazil, predicts trouble for control efforts in Africa, which rely almost entirely on praziquantel. The Schistosomiasis Control Initiative (SCI) is currently funding control support in Burkina Faso, Mali and Niger in West Africa and Zambia, Uganda and Tanzania in East Africa.   The goal of these programs is reduction in moribidity, not control of transmission.  In order to achieve this goal, treatment is distributed through schools or trained community drug distirubtors.  SCI will fund two mass-treatment campaigns, which will hopefully succeed in reducing prevalence and intensity of infection significantly.  In cases where transmission is high, a third cycle of mass-treatment may be necessary, and SCI has committed to establishing national control programs in each country to oversee this third cycle.  No molluscicides will be used in West Africa because of the cost and the potential for ecological consequences. 

Given the precedent set by China, West Africa will likely witness declines in schistosomiasis prevalence during the course of the mass-drug administration campaigns.  However, the persistence of those declines over times is doubtful. In order to ensure that control initiatives such as this one and others are sustainable, it is essential that the schistosomiasis control strategy emphasize the necessity of transmission control efforts such as molluscocides, or invest in the development of a vaccine to supplement chemotherapy. The rapid re-infection after treatment, the predicted expansion of schistosomiasis distribution due to global warming and water development projects, and the risk of drug resistance all demand that schistosomiasis control rely on something other than praziquantel alone.

Vaccine Development: An overview and demand for research

A vaccine against schistosomiasis could act in a number of ways.  It could prevent infection all together, it could reduce worm burden, or it could reduce egg fecundity.  Based on antigen candidates currently being researched, sterilizing immunity is unlikely, but a reduction in worm burden or egg fecundity is entirely possible.  Even if only a reduction in worm burden or fecundity is achieved, administering vaccines along with praziquantel will likely produce a much more long-lasting effect that can be achieved by using praziquantel alone. 

Schistosomes have developed highly complex immunoevasive strategies, which makes development of an entirely protective vaccine difficult. Out of 100 vaccine candidates identified, only 15% appear to offer any protectivity (Saddiqui 2008).  However, several factors suggest that vaccine development is hopeful.  First, humans living in endemic areas develop some degree of natural immunity, as well as some immunity after treatment (Bergquiest 2002).  It is believed that the parasite itself benefits from this “concomitant immunity,” since it prolongs the life of the host and therefore of the parasite (Siddiqui 2008). Second, irradiated cercariae confer 50-70%  protection in animal models with a single vaccination, and over 80% protection with two or three immunizations. Third, vaccine candidates already exist that produce >40% protection in animals. (Bergquist 2002).

            Several vaccine candidates exist for S. mansoni and to a lesser extent for S. haematobium. Three tetraspanins, four-transmembrane-domain proteins found on the schistosome tegument, have been identified as potential vaccine candidates: Sm23, SmTSP-1, SmTSP-2.  Both SmTSP-2 and Sm23 vaccines are suspected to have a protective role in humans based on studies with putatively resistant individuals.   Another membrane protein, Sm29 has been considered and is been found to be preferentially recognized by antibodies form putatively resistant rather than chronically infected individuals, although the effect is not as great as for TSP-2.  Only one vaccine, against haematobium, has entered clinical trials. Sm28-GST is a candidate that was shown in hamsters and rats to significantly reduce worm burdens and in primates to reduce fecundity.  Phase II clinical trails of Sh28-GST showed promising preliminary results, and trials will move towards evaluating clinical efficacy (Capron 2005).

Many japonicum antigens have also been identified for vaccine development.  Unlike with mansoni and haematobium, the zoonotic transmission of japonicum allows for an opportunity to create veterinary vaccines to use against reservoir hosts of S. japonicum.   In China, bovines are the major japonicum reservoirs and 90% of egg contamination comes from this source.  A human vaccine against schistosomiasis may still be needed though, especially considering that in the Philippines humans rather than animals are the principle cause of transmission (McManus 2008). 

Conclusion

Control of schistosomiasis remains a complex but critical initiative.  The morbidity and economic burden due to schistosomiasis is far greater than once surmised, yet control efforts directed toward the vast majority of these cases remain severely lacking.  Recently resources have been directed toward morbidity control.  While the use of praziquantel has been shown to be highly effective in reducing morbidity and severity of infection, high reinfection rates and low cure rates frequently prevent maintenance of any reduction in prevalence achieved by chemotherapy.  Thus, investments must be made in other control methods that can supplement chemotherapy.  Vaccines offer a promising means of achieving this goal.
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