Schistosomiasis – The Burden of Disease & Trends in Intervention
International Health Practice – 4/28/06
Schistosomiasis is a prevalent parasitic infection, with an
estimated 200 million people worldwide affected. While the distribution of infection has
changed, with 80-85% of current disease now found in sub-Saharan
This paper will cover prevalence of schistosomiasis, the complex life cycle of the organism responsible for schistosomiasis, pathogenesis, genital schistosomiasis, diagnosis and treatment, and lastly interventions that have been successful or which promise in future to lighten the burden of disease.
Who Suffers from Schistosomiasis?
Schistosomiasis was first
described in 1851 by Theodor Bilharz, after whom the disease was initially
named (bilharzia). (Ross et al, 2002).
Five species have been identified, of which the most commonly found
three will be discussed below. These are
Schistosoma mansoni, S. japonicum, and S.
haematobium. In general, S. mansoni is the most wide-spread. S.
haematobium is concentrated in Africa and the Middle East, while S. japonica is primarily found in
As shown in the WHO map
below, the vast majority of current schistosomiasis is found in sub-Saharan
Like most parasitic disease, schistosomiasis prevalence is related to poverty and poor living conditions (Engels et al, 2002) The poor rural population most at risk is more often than not co-infected with other parasites, such as hookworm and malaria. (Keiser, J., et. al., 2002).
Because of their play habits and hygiene, children are particularly at risk for infection. With each passing year, a child’s risk of infection increases, peaking between the ages of 10 and 20 (Kabatereine, N., et al, 2004). However, the intensity of their infection, as measured by quantitative egg counts of feces or urine, shows the heaviest burden in the youngest age group. The morbidity associated with childhood infection can result in cognitive and growth stunting that is irreversible (Nokes C, et al. l999).
Genital schistosomiasis is
a recently recognized complication of S.
haematobium. As will be discussed below, this particular species of
schistosomiasis primarily affects the urinary tract. However, it can also cause lesions in the
reproductive system, including cervicitis and uterine enlargement. Males can
also be affected, but symptoms are more subtle. One case-control study in
The Life Cycle of the Schistosome
As shown in figure 1, all infections follow direct contact with fresh water that harbors the larval form of the parasite, or cercaria. These require the “hospitality” of their intermediate host or vector, a specific fresh water snail. Once excreted by the snail, the infective, free-swimming cercariae then penetrates the intact skin of humans. The cercarial penetration can cause a papular, pruritic rash (schistosomal dermatitis or swimmer’s itch). This rash tends to be more severe in those with previous exposure. It may even cause edema, and massive cellular infiltrates in the dermis and epidermis. Most infected individuals, however, will remain asymptomatic.
In their human host’s subcutaneous tissue, the cercariae change into schistosomes, which migrate to the lung and thence to the liver to mature. The sexually mature adult, one or more months later, will be about 1-2 cm. It will now head for its preferred final anatomic home. For S. mansoni and S. japonicum, those are respectively inferior and superior mesenteric vessels. For S. haematobium, these are the perivesical and periureteral venous plexi that drain the ureters and bladder. There, the females, nestled in a groove at the edge of the male’s body, will lay fertilized eggs. From the small blood vessels where they are laid, the eggs will reach the lumen of the urinary tract or intestines. They will then be carried via urine or feces to the outside environment. If deposited in fresh water, they will hatch into motile miracidia. These miracidia will then infect their host, the
fresh water snail. They will divide asexually within the snail. Four-six weeks later, the snail will release the cercaria, which have matured, into the water, ready to look for new human hosts.
What is clear from this complex life cycle are the many steps required for infection to occur. The schistosomes require disposal of excretia (feces, or, in the case of S. haematobium, urine) into fresh water bodies, the presence of the fresh water snail, and water contact with the infected fresh water. Conversely, interruption of the life cycle may occur at several points. Each represents a possible opportunity for control of parasite burden.
The major pathology of schistosomiasis is chronic: retention of the eggs in host tissue causes chronic granulomatous injury. Eggs may be trapped at the site of deposition (intestines or, for S. haematobium, urinary bladder or ureters). This leads to local and systemic host responses. Lymphocyctes, macrophages, and eosinophils migrate to these magnets for inflammation, causing granulomas and, eventually, tissue destruction. The result will be fibrosis and obstruction.
Early symptoms of S. mansoni or S. japonicum may include colicky abdominal pain, bloody diarrhea, or no symptoms. There may be fibrosis of the intestinal wall and ulceration. There have been case reports of chronic constipation due to granulomas which obstruct the lumen of the intestines (Arthur, et. al, 1998.)
With longer periods of infection, correlating with great parasitic burden, hepatic granulomas may develop. Granulomas may cause fibrosis, but usually do not interfere with liver function until the passage of many years of heavy infection. Late findings include hepatosplenomegaly, portal hypertension, ascites and hematemesis. Co-infection with either hepatitis B or hepatitis C and S. mansoni, but not S. japonicum, are know to accelerate deterioration of hepatic function
S. haematobium can cause dysuria, hematuria, and urinary frequency early on. In highly endemic areas, more than 50% of children show moderate-severe urinary pathology. Even those with less parasitic burden have significant morbidity (Behrman and Vaughn, 2000.) Bladder involvement can result in hematuria, hypertension, obstructive uropathy, secondary urinary tract infections, and, ultimately, renal failure and even bladder cancer. Genital disease is present in approximately one third of infected women (Poggensee G., et al, 2001), resulting in a variety of vulvar and perineal disease, including ulcerative, fistulous, or wart-like lesions. As noted above, vulvar schistosomiasis may also facilitate the transmission of HIV (Feldmeier, H, 1995).
Acute schistosomiasis, or Katayama fever, is a severe, serum-sickness like syndrome characterized by fever, chills, eosinophilia, hepatosplenomegaly, and lymphadenopathy.
It most commonly affects older people who are heavily exposed to schistosomiasis for the first time. The onset of symptoms comes 4-8 weeks after exposure. Diagnosis
requires a high index of suspicion; symptoms procede oviposition. Diagnosis, therefore, cannot be made by screening urine or feces for eggs. Rather, serological testing are needed.
Eggs from any of the schistosomal species may also escape to the lungs, causing pulmonary hypertension or cor pulmonale. S. japonicum worms may migrate to the brain. Localized lesions there are associated with seizures.
The cornerstone of diagnosis of schistosomiasis is the detection of schistosome eggs in feces or urine. As the shedding of eggs fluctuates, up to three specimens may be required for diagnostic testing. These are generally observed in saline. For patients likely to have a smaller parasitic burden, such as returning travelers, formalin-based techniques improve the yield.
alternative method used in
Serological testing is helpful in acute schistosomiasis, where eggs are not to be found. However, the antibodies persist for months after parasitologic cure. Thus, they are sensitive, but not specific. Anyone who has been exposed will test positive for months or years. Antigen testing (based on urine, feces, or blood) is promising, but awaits field testing.
In areas that are highly endemic, the cost of testing is greater than the cost of treatment. In that setting, as will be discussed below, targeted universal treatment is recommended.
Other lab findings that support a diagnosis of schistosomiasis are eosinophilia, anemia, hypoalbuminemia, elevated urea and creatinine levels (for S. haematobium). A newer test of intensity of infection for S. haematobium is the eosinophilic cationic protein (ECP)..). Declining quantitative urinary ECP levels correlate with reduction in severity of illness. (Engels, D.et al, 2002) This test is particularly helpful for intestinal schistosomiasis. However, at $2.60 a dip-strip, this test is not currently feasible to use diagnostically. (Stothard, J., et al, 2006)
Ultrasound assessment of changes in the urinary system are also promising. While less straightforward in S. mansoni, ultrasound is still useful for early identification of of periportal fibrosis, and for assessment of hepatosplenomegaly.
In general, reliable markers for low-intensity infection are not available. As progress is made in reducing prevalence, and the focus shifts to control, rather than a difficult-to-achieve cure, such markers will be important. Without them, tracking the success of interventions is more difficult.
Single-dose monotherapy using praziquantel is used worldwide in community-based programs to control schistosomiasis. A dose of 40 mg/kg (divided into a twice-daily therapy for one day) cures 60-90% of S mansoni and S. haematobium. S. japonicum is generally treated with a dose of 60 mg/kg divided into 3 doses administered over a single day. Even in the minority who are not cured, worm burden and egg production are reduced. (Ross, et al, 2002). Thus, it is helpful for reducing the morbidity of chronic liver disease or bladder cancer. (Jurg Utzinger, et al, 2003)
Although the exact mechanism of action is not well understood, it is effective against adult worms. It is not, however, effective against the migrating larvae that are 3-21 days old. For this purpose, artemether, an antimalarial drug, is ideal. Given every two weeks during the transmission season, it can be used as an effective prophylactic drug. (Xiao S, 1996).
A third medication,
oxamniquine, has geographically limited effectiveness again S. mansoni. Although safe, and effective in South
America, the Caribbean and
Combination therapy using partner drugs with different mechanisms of action are of great interest, partly in the hope that their use may delay the emergence of resistence. Studies combining praziquantel and oxamnique have not consistently shown improvement over praziquantel alone. The utility of this combination will be further limited by oxamnique’s lack of efficacy in treating S. haematobium and S. japonicum.
By contrast, the combination of praziquantel and artemether is more promising. They target different stages of the worms’ life cycle, and show promise both in animal studies and clinical trials. The addition of artemether would also have the added benefit of controlling malaria. (There is some concern that there will be selective pressure on malaria if artemether becomes widely used. This could potentially limit its usefulness for malaria.)
J. Utzinger, in his excellent review of combination therapy for schistosomiasis (J. Utzinger , et. al, 2003), looks forward to “a new type of synthetic antimalarial drug“ active against all stages of all schistosomal species. That is something to watch for!
Strategies for Control
There are four main foci
for control of schistosomiasis: large-scale population-based chemotherapy,
vaccines, molluscicides, and environmental interventions. Various combinations of these strategies have
resulted in remarkable progress toward reducing schistosomiasis. Most formerly endemic countries of the
In areas of high prevalence, the availability of low-cost praziquantel has opened up the option of presumptive treatment based on early clinical symptoms, or universal treatment, especially of children. Current WHO initiatives target school-age children, with a goal of treating 75% of children at risk of schistosomiasis-related morbidty by 2010. (Bulletin of the WHO, 2002). Per WHO, “given the safety of the drugs, schoolteachers can be trained to administer them and record the number of children treated in each round.” Under this model, individual children are not screened.
Adults at high risk, such as farmers working in irrigation ditches, or freshwater fishermen, should also have access to praziquantel.
For areas of lower prevalence, questionnaire-based screening tools have proven valid. (Bergquist, Nils Robert, 2002) These have been used both to identify communities with high prevalence, and to identify individual cases who would then be further screened and treated, or treated presumptively.
Generating immunity through the use of vaccines is complex. In the presence of high prevalence, vaccine would not be given to naïve patients. Rather, those receiving the vaccine can be expected to have already been exposed, and to experience repeated exposure to schistosomiasis after getting the vaccine. It is precisely the host immune response that gives rise to the granulomas responsible for the morbidity of schistosomiasis. Potentially, by triggering the production of immunity to various schistosomiasis antigens, the vaccine could promote the production of granuloma formation. In fact, however, progress is being made in Phase 1 and 2 clinical trials of a S japonicum vaccine.
In much of
Even without eradication of schistosomes from the environment, the vaccine appears to reduce susceptibility to re-infection. It is postulated that the vaccine’s artificially-induced immunity is boosted by re-exposure to the not-yet-eradicated schistosomes. This suggests that immunogenicity may need to be assessed if and when schistosomes are eliminated.
Key to long term control
of schistosomiasis are improvements in hygiene and sanitation. By eliminating human waste in fresh water
bodies, part of the complex life cycle of the schistosome can be eliminated. In
Reduction of the snail population can be accomplished using molluscicides, or by introducing competing species which do not serve as vectors. Changes in the irrigation streams that make them less hospitable to the snails, such as lining channels with cement, are other options.
widespread throughout the developing
world, is now concentrated in
The success of many developing countries in controlling schistosomiasis encourages hope that in those areas still heavily burdened by the parasite, control is also possible. Furthermore, new initiatives and therapeutic tools, such as vaccine development, combination therapy, and targeted universal treatment, promise to move us closer to the day when schistosomiasis will be eradicated.
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