Schistosomiasis
– The Burden of Disease & Trends in Intervention
Ilana
Schmitt
International
Health Practice – 4/28/06
Introduction
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.
Pathogenesis
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.
Diagnosis
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.
An
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.
Treatment
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.
Vaccine Development
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.
Conclusion
Schistosomiasis, once
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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