Schistosomiasis

Transmission and life cycle

Individuals infected with Schistosoma release eggs into water via their feces or urine. A collection of stool samples under a microscope will show the eggs of S. intercalatum, S. mansoni, and S. japonicum. Looking at a urine sample under a microscope would reveal the eggs of S. haematobium and rarely, the eggs of S. mansoni. After larvae hatch from these eggs, the larvae infect a very specific type of freshwater snail. For example, in S. haematobium and S. intercalatum it is snails of the genus Bulinus, in S. mansoni it is Biomphalaria, and in S. japonicum it is Oncomelania. The schistosome larvae undergo the next phase of their lifecycles in these snails, spending their time reproducing and developing.

Once this step has been completed, the parasite leaves the snail and enters the water column. The parasite can live in the water for only 48 hours without a mammalian host. Once a host has been found, the worm enters its blood vessels. For several weeks, the worm remains in the vessels, continuing its development into its adult phase. When maturity is reached, mating occurs and eggs are produced. Eggs enter the bladder/intestine and are excreted through urine and feces and the process repeats. If the eggs are not excreted, they can become engrained in the body tissues and cause myriad problems such as immune reactions and organ damage. While transmission typically occurs only in countries where the freshwater snails are native, a case in Germany was reported where a man got schistosomiasis from an infected snail in his aquarium.

Humans encounter larvae of the schistosome parasite when they enter contaminated water while bathing, playing, swimming, washing, fishing, or walking through the water.

Life cycle

The life cycle stages are as follows:

1. The excretion of schistosome eggs in urine or feces depending on the species
2. The hatching of the eggs leads to the release of the free-swimming, ciliated larvae called miracidia
3. Miracidia find and penetrate the snails, which are the intermediate hosts (specific species of snails are dependent on the species of Schistosoma)
4. Within the snails, two successive generations of sporocysts occur
5. Sporocysts give rise to the infective free-swimming larvae with forked tails called cercariae, and they leave the snails to enter the water
6. Cercariae find the human hosts and penetrate their skin
7. Upon entrance into the human hosts, cercariae lose their tails and become schistosomulae
8. The schistosomulae travel to the lungs and heart via venous circulation
9. They migrate to the portal venous system of the liver where they mature into their adult form with two separate sexes
10. The adult male and female are paired together, exit the liver via the portal venous system, travel to the venous systems of the intestines or bladder (species dependent), and produce eggs.

Each species lays its eggs in specific parts of the body.

1. S. japonicum - superior mesenteric veins (but can also inhabit inferior mesenteric veins)
2. S. mansoni - inferior mesenteric veins (but can also inhabit superior mesenteric veins)
3. S. haematobium - vesicular and pelvic venous plexus of the bladder (occasionally rectal venules)
4. S. intercalatum and S. guineensis - inferior mesenteric plexus (lower portion of the bowels compared to S. mansoni)

Schistosomes can live an average of 3–5 years, and the eggs can survive for more than 30 years after infection.

Other hosts

Schistosomiasis is also a concern of cattle husbandry and mice. O-methylthreonine is weakly effective in mouse schistosomiasis but is not in use.

Pathogenesis

The infectious stage starts when the free-swimming larval form of the schistosome, cercariae, penetrates the human skin using their suckers, proteolytic enzymes, and tail movements; the cercariae transformed into schistosomulae by losing its tail and subsequently travels to the heart and lungs through the venous system until it eventually reaches the liver where it will mature into the adult form. The diseases caused by the schistomes are characterized into acute schistosomiasis and chronic schistosomiasis, and can vary dependent on the species of schistosome. Infection induces type 2 immune responses.

Acute infection

Minutes to days after initial infection:

• Cercerial dermatitis (Swimmer's itch) - swimmer's itch is caused by a localized allergic reaction at the sites of skin penetration by the cercariae causing an inflammatory reaction that is characterized by itchy red pimples and blisters.

Weeks to months after initial infection:

• Acute Schistosomiasis (Katayama's Fever) - the exact pathophysiology of this disease remains unknown. It has been hypothesized to be caused by a systemic immune response due to immune complex formation (Type III hypersensivity) with the foreign antigens on the migratory schistosomula and the eggs and the subsequent deposition of these complexes on various tissues leading to activation of an autoimmune response. Acute schistosomiasis caused by S. mansoni and S. haematobium generally affect people who have been infected for the first time such as tourists visiting endemic regions. In contrast, cases of acute schistosomiasis caused by S. japonicum can occur in reinfection to population who reside in endemic regions, and they occur in higher incidences and can have worse prognosis. It was proposed that the large amount of egg antigens released by S. japonicum interact with antibodies leading to the formation of a high volume of immune complexes, which cause enlargement of the lymph tissues. This sequence of events can lead to clinical manifestation of fever, enlargement of the spleen and liver due to fibrosis, portal hypertension, and death.

Chronic infection

The clinical manifestations of chronic infection are mainly caused by immune reaction to the eggs' entrapment within tissues resulting in granuloma formation and chronic inflammation. Adult worms live together in pairs (one male and female), sexually reproduce, and lay eggs in the veins around the intestines and bladder depending on the species, and these eggs can rupture the wall of the veins to escape to the surrounding tissues. The eggs make their way through the tissues to the intestinal or bladder lumen with proteolytic enzymes, however, a large number of eggs are unable to finish their journey and remained stuck within the tissues where they can elicit an immune response. The miracidia in these eggs can release antigens that stimulate an inflammatory immune response. The miracidia within the eggs live for around 6–8 weeks before they die and stop releasing the antigens. The granulomatous response is a cellular immune response mediated by CD4⁺ T cells, neutrophils, eosinophils, lymphocytes, macrophages, and monocytes, and this chronic inflammatory response elicited by the eggs can cause fibrosis, tissue destruction, and granuloma nodules that disrupt the functions of the organs involved. Th1 helper cell response is prominent releasing cytokines such as IFN-γ during the early phases of infection, and it transitions to Th2 response leading to increase in level of IgE, IL-4, and eosinophils as egg production progresses. In chronic infections, the Th2 response shifts to increasing the level of IL-10, IL-13, and IgG4, which reverses the progression of the granulomas and leads to collagen deposition at the sites of the granulomas. The specific clinical symptoms and severity of the disease this causes depends on the type of schistosome infection, duration of infection, number of eggs, and the organ at which the eggs are deposited. The number of eggs entrapped in the tissues will continue to increase if the Schistosoma are not eliminated.

Diagnosis

Identification of eggs in stools

Diagnosis of infection is confirmed by the identification of eggs in stools. Eggs of S. mansoni are about 140 by 60 μm in size and have a lateral spine. The diagnosis is improved through the use of the Kato-Katz technique, a semiquantitative stool examination technique. Other methods that can be used are enzyme-linked immunosorbent assay, circumoval precipitation test, and alkaline phosphatase immunoassay.

Microscopic identification of eggs in stool or urine is the most practical method for diagnosis. A stool examination should be performed when infection with S. mansoni or S. japonicum is suspected, and a urine examination should be performed if S. haematobium is suspected. Eggs can be present in the stool in infections with all Schistosoma species. The examination can be performed on a simple smear (1 to 2 mg of fecal material). Because eggs may be passed intermittently or in small numbers, their detection is enhanced by repeated examinations or concentration procedures, or both. In addition, for field surveys and investigational purposes, the egg output can be quantified by using the Kato-Katz technique (20 to 50 mg of fecal material) or the Ritchie technique. Eggs can be found in the urine in infections with S. haematobium (recommended time for collection: between noon and 3 PM) and with S. japonicum. Quantification is possible by using filtration through a nucleopore filter membrane of a standard volume of urine followed by egg counts on the membrane. Tissue biopsy (rectal biopsy for all species and biopsy of the bladder for S. haematobium) may demonstrate eggs when stool or urine examinations are negative.

Confirming microhematuria in urine using urine reagent strips is more accurate than circulating antigen tests to identify active schistosomiasis in endemic areas.

Antibody detection

Antibody detection can be useful to indicate schistosome infection in people who have traveled to areas where schistosomiasis is common and in whom eggs cannot be demonstrated in fecal or urine specimens. Test sensitivity and specificity vary widely among the many tests reported for the serologic diagnosis of schistosomiasis and depend on the type of antigen preparations used (crude, purified, adult worm, egg, cercarial) and the test procedure.

At the U.S. Centers for Disease Control and Prevention, a combination of tests with purified adult worm antigens is used for antibody detection. All serum specimens are tested by FAST-ELISA using S. mansoni adult microsomal antigen. A positive reaction (greater than 9 units/μL serum) indicates infection with Schistosoma species. Sensitivity for S. mansoni infection is 99%, 95% for S. haematobium infection, and less than 50% for S. japonicum infection. The specificity of this assay for detecting schistosome infection is 99%. Because test sensitivity with the FAST-ELISA is reduced for species other than S. mansoni, immunoblots of the species appropriate to the person's travel history are also tested to ensure detection of S. haematobium and S. japonicum infections. Immunoblots with adult worm microsomal antigens are species-specific, so a positive reaction indicates the infecting species. The antibody's presence only indicates that schistosome infection occurred at some time and cannot be correlated with clinical status, worm burden, egg production, or prognosis. Where a person has traveled can help determine which Schistosoma species to test for by immunoblot.

In 2005, a field evaluation of a novel handheld microscope was undertaken in Uganda for the diagnosis of intestinal schistosomiasis by a team led by Russell Stothard from the Natural History Museum of London, working with the Schistosomiasis Control Initiative, London.

Molecular diagnostics

Polymerase chain reaction (PCR) based testing is accurate and rapid. However, it is not frequently used in countries where the disease is common due to the cost of the equipment and the technical expertise required to run the tests. Using a microscope to detect eggs costs about US$0.40 per test whereas PCR is about $US 7 per test as of 2019. Loop-mediated isothermal amplification are being studied as they are lower cost. LAMP testing is not commercially available as of 2019.

Laboratory testing

S. haematobium screening in the community can be done by using urine dip-stick to check for hematuria, and the stool guaiac test can be used to test for blood in the stool for potential S. mansoni and S. japonicum infection. For travelers or migrants in endemic regions, complete blood count with differential can be used to identify a high level of eosinophil in the blood, which could be indicative of an acute infection. Liver function test can be ordered if hepatosplenic schistosomiasis is suspected, and a subsequent hepatitis test panel can be ordered if liver function test is abnormal.

Like most parasitic infections, schistosomiasis will usually cause significant eosinophilia that can be identified on a complete blood count with differential.

Tissue biopsy

If other diagnostic methods of schistosomiasis have failed to detect the infection, but there is still a high suspicion for schistosomiasis, tissue biopsy from the rectum, bladder, and liver can be obtained to look for schistosome eggs within the tissue samples.

Imaging

Imaging modalities such as X-rays, ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI) can be utilized to evaluate for severity of schistosomiasis and damages of the infected organs. For example, X-ray and CT scans of the chest can be used to detect lesions in the lungs from pulmonary schistosomiasis, and pelvic X-ray can reveal calcification of the bladder in chronic urinary schistosomiasis. Ultrasound may be used to look for abnormalities in the liver and spleen in hepatosplenic schistosomiasis, and CT scan of the liver is a good tool to look for calcification in the liver associated with S. japonicum infection. CT scan can also be used to assess damages from the schistosomiasis infection in the intestinal, urogenital, and central nervous system. MRI is used to evaluate schistosomiasis of the central nervous system, liver, and genital.

PET/CT scans that identify tissues with higher metabolic activity have been used to help diagnose schistosomiasis in rare cases. This is due to the high level of inflammation caused by the schistosomal eggs, which increases the metabolic rate of the surrounding tissues.

Prevention

Many countries are working towards eradicating the disease. The World Health Organization is promoting these efforts. In some cases, urbanization, pollution, and the consequent destruction of snail habitat have reduced exposure, with a subsequent decrease in new infections. The elimination of snail populations using molluscicides had been attempted to prevent schistosomiasis in the past, but it was an expensive process that often only reduced but did not eliminate the snail population. The drug praziquantel is used for prevention in high-risk populations living in areas where the disease is common. The Centers for Disease Control and Prevention advises avoiding drinking or coming into contact with contaminated water in areas where schistosomiasis is common.

A 2014 review found tentative evidence that increasing access to clean water and sanitation reduces schistosome infection.

Other important preventive measures include hygiene education leading to behavioral change and sanitary engineering to ensure a safe water supply.

Preventive anthelminthic administration

For schistosomiasis control, the World Health Organization recommends preventive anthelminthic administration, which is the treatment of an entire affected population and the periodic treatment of all groups at high risk of acquiring schistosomiasis by using Praziquantel. In 2019, 44.5% of people with schistosomiasis were treated globally, and 67.2% of school-aged children needing preventive chemotherapy received treatment.

Snails, dams, and prawns

For many years from the 1950s onwards, vast dams and irrigation schemes were constructed, causing a massive rise in water-borne infections from schistosomiasis. The detailed specifications in various United Nations documents since the 1950s could have minimized this problem. Irrigation schemes can be designed to make it hard for the snails to colonize the water and to reduce contact with the local population. Even though guidelines on how to design these schemes to minimise the spread of the disease had been published years before, the designers were unaware of them. The dams appear to have reduced the population of the large migratory prawn Macrobrachium, which eats the snails. After the construction of fourteen large dams, greater increases in schistosomiasis occurred in the historical habitats of native prawns than in other areas. Further, at the 1986 Diama Dam on the Senegal River, restoring prawns upstream of the dam reduced both snail density and the human schistosomiasis reinfection rate.

Integrated strategy in China

In China, the national strategy for schistosomiasis control has shifted three times since it was first initiated: transmission control strategy (from mid-1950s to early 1980s), morbidity control strategy (from mid-1980s to 2003), and the "new integrated strategy" (2004 to present). The morbidity control strategy focused on synchronous chemotherapy for humans and bovines and the new strategy developed in 2004 intervenes in the transmission pathway of schistosomiasis, mainly including replacement of bovines with machines, prohibition of grazing cattle in the grasslands, improving sanitation, installation of fecal-matter containers on boats, praziquantel drug therapy, snail control, and health education. A 2018 review found that the "new integrated strategy" was highly effective in reducing the rate of S. japonicum infection in both humans and the intermediate host snails and reduced the infection risk by 3–4 times relative to the conventional strategy.

Treatment

Two drugs, praziquantel and oxamniquine, are available for the treatment of schistosomiasis. They are considered equivalent in relation to efficacy against S. mansoni and safety. Historically, antimony potassium tartrate remained the treatment of choice for schistosomiasis until the development of praziquantel in the 1980s. Because of praziquantel's lower cost per treatment and oxaminiquine's lack of efficacy against the urogenital form of the disease caused by S. haematobium, praziquantel is generally considered the first option for treatment. Praziquantel can be safely used in pregnant women and young children. The treatment objective is to cure the disease and prevent the progression of the acute to chronic form of the disease. All cases of suspected schistosomiasis should be treated regardless of presentation because the adult parasite can live in the host for years.

Schistosomiasis is treatable by taking a single dose of the drug praziquantel by mouth annually.

Praziquantel eliminates the adult schistosomes but does not kill the eggs and immature worms. Live eggs can be excreted by the infected individuals for weeks after treatment with praziquantel. The immature worms can survive and grow into adult schistosomes after praziquantel therapy. Thus, it is important to have repeated schistosomiasis testing of the stool and/or urine around 4–6 weeks after praziquantel therapy. Praziquantel treatment may be repeated to ensure complete parasite elimination.

The WHO has developed guidelines for community treatment based on the impact the disease has on children in villages in which it is common:

• When a village reports more than 50 percent of children have blood in their urine, everyone in the village receives treatment.
• When 20 to 50 percent of children have bloody urine, only school-age children are treated.
• When fewer than 20 percent of children have symptoms, mass treatment is not implemented.

Other possible treatments include a combination of praziquantel with metrifonate, artesunate, or mefloquine. A Cochrane review found tentative evidence that when used alone, metrifonate was as effective as praziquantel. Mefloquine, which has previously been used to treat and prevent malaria, was recognised in 2008–2009 to be effective against schistosomes.

Post-treatment monitoring Osteopontin (OPN) is a promising tool for monitoring praziquantel efficacy and post-treatment fibrosis regression as (OPN) expression is modulated by S. mansoni egg antigens and its levels correlate with the severity of schistosomiasis fibrosis and portal hypertension in mice and humans. Praziquantel pharmacotherapy reduces systemic OPN levels and liver collagen content in mice.

Epidemiology

The disease is found in tropical countries in Africa, the Caribbean, eastern South America, Southeast Asia, and the Middle East. S. mansoni is found in parts of South America and the Caribbean, Africa, and the Middle East; S. haematobium in Africa and the Middle East; and S. japonicum in the Far East. S. mekongi and S. intercalatum are found locally in Southeast Asia and central West Africa, respectively.

The disease is endemic in about 75 developing countries and mainly affects people living in rural agricultural and peri-urban areas.

Infection estimates

In 2010, approximately 238 million people were infected with schistosomiasis, 85 percent of whom live in Africa. An earlier estimate from 2006 had put the figure at 200 million people infected. As of the latest WHO record, 236.6 million people were infected in 2019. In many affected areas, schistosomiasis infects a large proportion of children under 14 years of age. An estimated 600 to 700 million people worldwide are at risk from the disease because they live in countries where the organism is common. In 2012, 249 million people needed treatment to prevent the disease. This likely makes it the most common parasitic infection with malaria second and causing about 207 million cases in 2013.

S. haematobium, the infectious agent responsible for urogenital schistosomiasis, infects over 112 million people annually in Sub-Saharan Africa alone. It is responsible for 32 million cases of dysuria, 10 million cases of hydronephrosis, and 150,000 deaths from kidney failure annually, making S. haematobium the world's deadliest schistosome.

Deaths

Estimates regarding the number of deaths vary. Worldwide, the Global Burden of Disease Study issued in 2010 estimated 12,000 direct deaths while the WHO in 2014 estimated more than 200,000 annual deaths related to schistosomiasis. According to the Global Burden of Disease Study 2021, the number of deaths related to schistosomiasis in 2021 was 12,858 people. Another 20 million have severe consequences from the disease. It is the most deadly of the neglected tropical diseases.

History

The most ancient evidence of schistosomiasis dates back to more than 6,000 years ago. Studies conducted on human skeletal remains found in northern Syria (5800–4000 BC) demonstrated evidence of a terminal spined schistosome from the pelvic sediment of skeletal remains. Even though this evidence comes from the Middle East, it has been suggested that the 'cradle' of schistosomes lies in the region of the African Great Lakes, an area in which both the parasites and their intermediate hosts are in an active state of evolution. Subsequently, it is believed that schistosomiasis spread to Egypt as a result of the importation of monkeys and slaves during the reign of the fifth dynasty of the Pharaohs (ca. 2494–2345 BC).

Schistosomiasis is known as bilharzia or bilharziosis in many countries, after German physician Theodor Bilharz, who first described the cause of urinary schistosomiasis in 1851.

The first physician who described the entire disease cycle was the Brazilian parasitologist Pirajá da Silva in 1908. The earliest case known of infection was discovered in 2014, belonging to a child who lived 6,200 years ago.

The disease was a common cause of death for Egyptians in the Greco-Roman Period.

In 2016, more than 200 million people needed treatment, but only 88 million people were actually treated for schistosomiasis.

Etymology

Schistosomiasis is named for the genus of parasitic flatworm Schistosoma, a term which means 'split body'. The name Bilharzia comes from Theodor Bilharz, a German pathologist working in Egypt in 1851 who first discovered these worms. The name Katayama disease comes from the Katayama district of Hiroshima Prefecture in Japan, where schistosomiasis was once endemic.

Prevalence in Egypt

Because of its prevalence in Egypt dating back millenia, the schistosomiasis symptom of blood in the urine was considered to be the male version of menstruation, and was still viewed as a rite of passage for boys in the early 20th century.

The prevalence of Schistosomiasis in Egypt was exacerbated by the country's dam and irrigation projects along the Nile river. From the late 1950s through the early 1980s, infected villagers were treated with repeated injections of tartar emetic. Epidemiological evidence suggests that this campaign unintentionally contributed to the spread of hepatitis C via unclean needles. Egypt has the world's highest hepatitis C infection rate, and the infection rates in various regions of the country closely track the timing and intensity of the anti-schistosomiasis campaign.

Among human parasitic diseases, schistosomiasis ranks second behind malaria in socio-economic and public health importance in tropical and subtropical areas.

Research

A proposed vaccine against S. haematobium infection called "Bilhvax" underwent a phase 3 clinical trial among children in Senegal. The results, reported in 2018, showed that it was ineffective despite provoking some immune response. Using CRISPR gene editing technology, researchers decreased the symptoms due to schistosomiasis in an animal model.

Using thromboelastography, researchers at Tufts University observed that murine blood incubated by adult worms for one hour has a coagulation profile similar to that of patients that have hemophilia or on anti-coagulant drugs, suggesting that schistosomes could possess anti-coagulant properties. Inhibiting schistosome activity in blood coagulation could potentially serve as a therapeutic option for schistosomiasis.