Schistosomiasis

The World Health Organization has targeted a number diseases on which to focus
support and research effort.

These diseases are:

• Malaria,
• Schistosomiasis (bilharzia or "snail fever"),
• Leishmaniasis,
• African trypanosomiasis (sleeping sickness),
• American trypanosomiasis (Chagas disease),
• Lymphatic filariasis (which leads to elephantiasis),
• Onchocerciasis (river blindness)
• Leprosy.

Over 500 million people, almost all of them in the developing countries, suffer from
these diseases, which can cause terrible anguish, deformity, and death. At the same time
they cause considerable economic losses, and frequently interfere with development
projects (particularly water projects such as dams and irrigation schemes, and planned
and unplanned forestry).

The death toll from the diseases - particularly among african children suffering from
malaria - is expected to double by 2010, possibly reaching four million lives a year,
unless radical solutions are found. Population increase, the spread of parasite resistance,
mass migrations, environmental disturbance, and disruption of control programmes
through economic devastation, civil unrest and wars, all contribute to the tropical disease
problem.

Schistosomiasis, also known as bilharzia or snail fever, infects in excess of 200 million
people and results in severe morbidity and mortality.

It is principally a disease of tropical and sub-tropical regions and is found in South and
Central America, Africa, Asia and south East Asia.

There are three main species of schistosomes infecting humans, S. mansoni, S. japonicum
which inhabit the mesenteries around the intestine and S. haematobium which are found
in the venules surrounding the bladder.
Life cycle

Among the digenea, schistosomes are unusual in that the are dioecious, having separate
males and females. They are located in the mesenteric veins. The males are significantly
larger than females. The females lie inside a ventral fold in the tegument of the males
called the gynecophoral canal. Worms pair as young juveniles in the liver and remain so
for life. The eggs which measure 140 x 60 µm, are not operculate, and have a distinctive
shape and spine. The position of the spine is characteristic of the species.

The eggs are responsible for much of the pathology associated with the disease.
How do the eggs exit to the exterior?

The eggs pass through the walls of the mesenteries, and through the intestinal walls into
the gut lumen. How they achieve this is still not well understood, however, it is likely to
be a result of a number of interacting factors. Physical factors such as the mechanical
action of the egg spine, acted upon initially, by the host blood pressure and then by the
peristaltic action of the gut help drive the egg into and through the tissues. In addition, the
miracidium within the egg has been shown to release proteolytic enzymes which may
help it digest its way through the host tissue. The host inflammatory reaction, which is a
delayed type hypersensitivity reaction and which forms a granuloma around the egg, also
seems to be essential for successful migration of the egg to the lumen of the intestine.
Experimental infections in mice given anti-inflammatory agents results in reduced
granuloma formation with the eggs becoming trapped in the intestinal tissue.

Not all the eggs pass out via the intestine. Many of the eggs are swept back to the liver
where they are trapped and form liver granuloma.

In general, there is 6 day period between the time the schistosome eggs are laid and they
leave the host, by which time they are fully embryonated and ready to hatch. There are
three principal factors which are important in the hatching of schistosoma eggs:

• Temperature ( 25-30 C),

• Light, and
• Osmotic pressure.

On entering a hypotonic environment (water) the increase in the osmotic pressure as

water enters the egg and the activation of the enzyme leucine amino peptidase , in hibited
by NaCl, results in rupture of the egg shell . (Note: when isolating schistosome eggs from
mouse livers the eggs are maintained in isotonic saline, 0,85%, preventing them from
immediately hatching) The egg, which is mechanically ruptured along its long axis,
releases a highly motile (2 mm/sec) ciliated miracidium which measures approximately
150-180 m in length.

(It is noteworthy that the sex of the adult worms which will eventually be produced from
the miracidium is already determined at this stage. Therefore, if a snail is infected with a
single miracidium all the resulting cercariae will produced adults worms in the definative
host which are either all male or all female.)

The miracidium searches out and penetrates the snail intermediate host. It can remain
infective for 8 - 12 hr. To increase the chance of the miracidia locating the host, it has a
negatively geotactic and positively phototactic behavioural response which tends to place
it in the general environment of the snail host, Biomphalaria glabrata. Chemical
attractants from the snail such as mucus, long chain fatty acids and even amino acids
attract the miracidia. Recently, it has been discovered that amines such as dopamine are
also highly attractive to the miracidia.
After the miracidia makes contact with the snail there is a period of exploratory
behaviour prior to penetration. Seventy percent of the miracidia appear to penetrate
through the foot of the snail, other penetration sites include the tentacles and the edge of
the mantle.

Penetration is a combination of mechanical motion of the apical papillae and histolytic

secretions released from the penetration glands. The cilia are not lost until after
penetration is complete. The location of the next stage within the snail, the sporocyst, is
dependent on the schistosome species.

• S. mansoni - at the site of penetration, usually the foot.

• S. haematobium - same as above
• S. japonicum - there is a preference for cavity organs , viscera and heart.

The sporocyst undergoes development and produces by 35-600 daughter sporocysts after
about 3 weeks. The daughter sporocysts migrate to the digestive glands of the snails and
produce the next infective stage, the cercaria. The mean cercarial output from an infected
snail has been estimated to be about 1500/day and this last for up to about 18 days. The
period from penetration of the snail to release of the cercariae is about 4 weeks. The
cercariae are released on a circadian (24 hr) cycle during daylight hours.

It has been determined that the pattern of cercarial shedding is dependent on the focus of
the infection and the behaviour of the host population. In one study in Guadeloupe island,
where there was both a human and a sylvatic focus of infection, three different shedding
patterns were obtained in different regions. In the urban area, the human population were
the focus of infection, cercariae were shed early in the morning. In a remote country area
where the focus of the infection cycled through sylvatic hosts the cercarial shedding
pattern occurred in late afternoon. However, in a rural community where there both
humans and rodents acted as hosts, the shedding pattern was found to be intermediate to
the other two.

The cercaria are very active, non-feeding stages which rely on stored glycogen food
reserves. These reserves appear to vary considerably (4.8 - 14.2 ng of glycogen
/cercariae) and may depend on the nutritional state of the snail and level of infection.

Glycogen reserves in the cercaria have been shown to decline in a negative exponential
manner with time after shedding. The rate of loss is, not surprisingly, greater in the tail
than the rest of the cercarial body.

Host location

Once released from the snail, periodic bursts of activity keep the cercariae just under the
surface of the water. As well as these endogenously driven bursts of activity, sudden
shadows also evoke cercarial activity. Once in close contact with the next host, products
released from the skin have a dramatic effect on the cercarial behaviour causing
continuous swimming motion interspersed with frequent reversals which is a typical
example of what is known as klinokinetic behaviour.

Penetration

Penetration into the host skin has three distinct phases:

1. Attachment
2. Creeping over the skin surface - exploratory behaviour

Both these behaviours are triggered by chemical and thermal stimuli.

Penetration into the epidermis - This is in response to chemical stimuli, products are
aliphatic hydrocarbons, probably free fatty acids, on the skin produced by bacterial
esterases working on tri-glycerides.

The actual penetration is a combined mechanical and secretory process the initial phase
of which may take as little as a few minutes. As penetration proceeds there are structural
and physiological changes which occur and accompany the transformation of a free-
living infective stage to a parasitic larval schistosomulum.

Structural changes - these take less than 1 hr.

1. Change in outer membrane. The cercarial tegument is bounded by a classic

trilaminate plasma membrane which has a 1-2 m thick glycocalyx. This outer
surface coat is mostly shed with the tail at the time of penetration.
2. The various penetration glands empty.
3. The Tegumental cell bodies which lie beneath the muscular layer release
membranous vesicles which pass into the tegumental cytoplasm and form a multi-
laminate tegumental surface, replacing the tri-laminate membrane.
4. In addition, oesophageal glands release their contents into the oesophageal lumen
heralding the start of feeding.

This transformation process requires two physiological triggers, elevated temperatures

and iso-osmotic conditions. The glycocalyx is thought to control the surface permeability
in fresh water and its loss coincides with osmotic sensitivity.

Biochemical changes

As well as physical changes there are a variety of biochemical changes which also take
place during this transformation from free-living to parasitic form. There is a switch in
the larval energy metabolism over the first 24 h from an aerobic glycogen base
metabolism to a predominately anaerobic one which is accompanied by an increase in
lactate production. Also during this first 24 h, there is a remarkable turnover of surface
molecules on the schistosomula surface. As time passes there is the appearance of more
surface molecules which have low reactivity, in terms of stimulating the hosts immune
system. By 24-48 hours the schistosomula has become completely refractory to antibody
mediated immune cell cytotoxicity. In addition to providing molecules on the surface
which mask antigenic epitopes, the schistosomula surface also has the ability to coat itself
with host molecules. Host erythrocyte surface glycolipids are adsorbed onto the
schistosomula surface helping to mask sensitive parasite epitopes from the host defenses
system.

The parasite enters the initial epidermal layer of the skin very rapidly (less than 30 min)
and then come to rest when they reach the dermis which appears to present a temporary
barrier to further penetration. They remain at this location for about 40 hours. Once
through the dermis they locate a venule within about 10 hours and require a further 8
hours to penetrate the venule wall. Once in the blood capillaries the schistosomula are
carried to the first capillary bed, the lungs, where they become lodged and double in size
over the next few days. This so called lung phase lasts from 3-8 days. Following this
period the larvae make there way to the liver, the exact root is unknown. Upon reaching
the liver the schistosomula mature to young adults pairing between 28-35 days post-
infection. When the worms are mature the paired adults migrate out of the liver to the
mesenteries where the female begins egg laying. The male and female worms remain in
close association, the slender female lying in a ventral groove on the male surface called
the gynecophoral canal. This is an intimate association with the female receiving
products, such as glucose, trans-membranously from the male. The importance of the
association is highlighted by the fact that if the female fails to mate it does not mature
properly and remains stunted. It has been estimated that in human infections adult worms
can survive in the host for 20-30 years.

Parasite success rate

In the mouse model system only about 20% of the initial cercarial inoculum makes it to
the adult stage. Although there has been much controversy over the site of attrition of the
larval worms, it now seems clear that the greatest loss of larval stages occurs during the
migration through the lungs, with relatively small losses during migration through the
skin.

Fate of the Schistosome Eggs

Although many of the eggs pass through the gut mucosa and exit the host with fecal
material, as many as 50% of the eggs can be swept by the blood stream back to the liver,
where they become lodged in the liver parenchyma. The lodged eggs cause the host
inflammatory response leading to granuloma formation and liver fibrosis, and is the chief
cause of pathology.

Pathology of Schistosome Infections

The pathology associated with a schistosome infection arises primarily from the
schistosome eggs ( single sex infections, thus no egg production , cause little pathology),
both those in the intestine and those swept back by the blood to the liver, and on occasion
to other tissues such as the brain and lungs. At least 50% of the eggs laid fail to reach the
exterior.

Clinical signs of the disease take on different phases:

• Acute
• Chronic - subclinical
• Severe - symptomatic

Acute Schistosomiasis

The acute stage, often known as Katayama fever, is normally found in young children or
young adults with no previous exposure to the disease, and is particularly prevalent in
individuals with S. japonicum infections. The acute reaction is in response to the sudden
high level of antigen exposure and is usually associated with the onset of egg deposition.
Clinical symptoms consists of skin rashes, asthma-like episodes, daily fever, malaise,
diarrhoea, swollen lymph nodes and aching joints and a number of other non-specific
symptoms. Pathologically one sees large florid granuloma with a rich infiltration of
eosinophils. Frequently, heavy infections can lead to fibrotic chronic schistosomiasis or
the death of the patient.

Chronic Schistosomiasis

In chronic schistosomiasis the patient experiences diarrhoea and fevers. In children the
infection can depress their growth rate. The infection also leads to enlargement of the
liver and spleen. Fibrosis of the liver can result in portal hypertension,
hepatosplenomegaly, ascites formation, oesophageal varices leading to fatal hematemesis
( vomiting blood).

In S. haematobium, fibrosis of the bladder may lead to ureteric obstruction,

pyelonephritis and hydronephrosis leading to renal failure.

Granuloma formation
After egg deposition, which occurs predominantly in the periportal area, the egg, over
about a 16 day period becomes surrounded by a dense infiltrate composed of mainly
lymphocytes, macrophages and a variable number of eosinophils, held together in a
extracellular matrix. In athymic mice such lesions do not occur, suggesting that there is a
strong T-cell regulation of the granuloma response. Whereas mice with impared B-cell
function still exhibits normal granuloma formation. Therefore Granuloma formation is a
T-cell dependent and t-cell mediated process.

Eggs measure up to 70 m in width and therefore cannot traverse the capillary beds as the
blood flows through the liver. Granuloma size and cell composition vary depending on
the schistosome species, host species and the intensity and duration of the infection, and
even the tissue location can have an impact on granuloma size. The principal factor
however, is how immunoresponsive the host is to the schistosome egg antigen. Although
some of the tissue response is due to the physical presence and damage by the egg, the
majority of the pathology is due to the host response to the soluble egg antigens which
are released through submicroscopic egg shell pores.

In normal hosts, reactivity to SEA - soluble egg antigens, peaks early, producing large
florid lesions but as the infection becomes more chronic, i.e. by 8-10 weeks post
infection, granulomas tend to become relatively smaller due to a modulation of the host
hypersensitivity response.

Activated T-helper cells are instrumental in the induction of IL2, which is the principle
cytokine required for the formation of normal granulomas. Down regulation of the
production of this cytokine is initiated by a subset of suppressor-inducer T-cells.
Modulation of these granulomas is immunologically complex.

To summarize, immunoregulation of the granulomas requires multiple effector systems

working in concert, which achieves a deceptively simple host adjustment to the persistent
generation of parasite antigens. This modulation can be regarded as beneficial to the long
term maintenance of the adult parasite and its life cycle. It is obvious a delicate balance.
If there was no immuno-depression it would lead to a rapid death of the patient. Complete
immunosuppression on the other hand results in low egg excretion and eggs with
defective metabolism and also leads to high host mortality.

Concomitant Immunity

Concomitant immunity has long been considered a feature of schistosome infections and
describes the phenomenon where by the adult worms can survive happily in the
mesenteric veins where as the host seems to be resistant to secondary infection. What is
responsible for this type of immunity?

Experimental evidence in the mouse-schistosome model suggested that concomitant

immunity was due to non-immune processes. Wilson and co-workers suggested the
hepatic shunt theory. As previously mentioned, as an infection proceeds there is a
gradual build up of eggs in the liver which clogs the intra-hepatic circulatory system.
These workers found that as a result of this blockage both intra and extra hepatic
astamosis occurred such that the blood flow was shunted around these obstructions.
These by-passes usually occurred in vessels of larger diameter such that the
schistosomula on leaving the lungs were swept past the liver, where they would normally
be trapped by the capillary bed and complete their development, and instead passed to
other sites and eventually died. The researchers demonstrated this by injecting
polystyrene beads of known diameter and showing that they ended up in sites other than
the liver, once a critical threshold number of eggs were deposited in the liver. However,
whether this occurs in human infections, or is a peculiarity of the mouse model system, is
not clear. Given the enormous size of the human liver in comparison to the mouse and
therefore its greater capacity to sustain higher egg burdens it seems less likely that this
would be the only mechanism resulting in the concomitant immunity.

Epidemiological studies have demonstrated a pattern of age related immunity to

reinfection which is not consistent with that which would be observed with normal non-
sterile immunity. The bell shaped curve on the age-prevalence curve shown below
suggests resistance due to acquired immunity or as a result of a change in the pattern of
water contact.(It is well known that in general, children tend to play in water and
therefore have more frequent contact with infective stages than the adult population.)
There is some evidence for age related resistance to schistosomiasis:

1. Some heavily infected individuals, after treatment do not become re-infected.

Resistance is not demonstrable in children under 10 years but increases progressively
with age.

2. Some studies have demonstrated an association between of high levels of eosinophilia

and resistance to re-infection.

3. Children under the age of 10 are readily re-infected after treatment, demonstrating a
lack of resistance. This is as a result of increased levels of circulating IgM antibody
which bind to the schistosomula, and as a result, blocks or masks the binding site for IgG
antibody. IgG is important for initiating antibody-dependant cell-mediated cytotoxicity by
eosinophils and macrophages. The level of IgM production decreases as the child ages
which coincides with increase resistance to infection.

Diagnosis

The most obvious method of diagnosis is the identification of eggs in the stool for S.
mansoni and S japonicum or in the urine for S haematobium. For these types of diagnosis
a simple faecal smear is often inadequate, therefore, some type of egg concentration
technique is require. If no eggs are found, but the outward symptoms are suggestive of
schistosomiasis, then rectal, liver or bladder biopsies may be necessary.

An intradermal skin test using schistosome antigen has been found to be a fairly sensitive
immunological test. But this test will not show positive until the patient has been infected
for 4-8 weeks.

The circum-oval precipitation test has also been found to be fairly sensitive and is
particularly useful for determining if treatment has been successful, because the test
becomes negative after all the eggs in the tissue have been killed. The test depends on
observing the formation of a precipitate around isolated schistosome eggs in the presence
of sera from infected individuals.

Treatment and Control

Drug treatment is still the principal method of control and the drug of choice is
praziquantel. However the degree of recovery from the infection depends on the extent of
the damage caused by the infection. If extensive fibrosis has occurred this cannot be
reversed and therefore there is permanent liver damage. In addition the efficacy of
praziquantel seems to depend on the patients prior exposure to the disease. Recently it
has been found that certain populations, not previously exposed to schistosomiasis,
respond poorly to the praziquantel treatment, their immune systems are not primed. It
seems that the mode of action of praziquantel is such that to be fully effective it requires
the participation of the patients immune system.
The control of schistosomiasis other than with the use of drug therapy is difficult and as
yet there is no effective vaccine. Other methods of control which have been tried are:

• Drainage of marsh areas where snails breed

• Improved sanitation
• Education
• The use of molluscicides
• Introduction of bio-control agents, such as predatory snails

Swimmers Itch

Many species of flukes belonging to the family schistosomatidae are parasitic in birds
and in other animals, and many snails harbour the developmental stages of these
parasites. Cercaria from various different species of these bird schistosomes
(Trichobilharzia, Gigantobilharzia, Ornithobilharzia) may be found in large numbers in
freshwater streams ponds or lakes in North America. These cercaria often attempt to
penetrate vertebrates which are not the normal hosts. The penetrating cercaria do not
survive but produce and intense inflammatory reaction resulting in dermatitis with
intense itching often known as swimmers itch.