Schistosomiasis

• 1. Introduction

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  Schistosomiasis, also called snail fever, infected an estimated 236.6 million people in 2019. People catch it through contact with fresh water that looks like any other stream, pond, or irrigation channel. Somewhere in that water, a microscopic larva has left a snail and is searching for skin. Once it finds some, it begins a trip through the veins that can end in a damaged liver, a failing kidney, or seizures. How does a flatworm depend on a snail to reach a human body? Why can the same infection cause a passing rash in one person and bladder cancer in another? And why did some of the largest water projects, built from the 1950s onward, make the problem worse?

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• 2. Snail Relay

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  Three genera of freshwater snail keep this disease alive. Bulinus hosts S. haematobium and S. intercalatum, Biomphalaria hosts S. mansoni, and Oncomelania hosts S. japonicum. Each parasite species accepts only its own kind of snail.

  Miracidia, the ciliated larvae that hatch from eggs passed in urine or feces, are the first swimmers in the cycle. A miracidium finds a snail and enters it. Inside, two successive generations of sporocysts develop. These give rise to cercariae, larvae with forked tails that leave the snail and swim into open water.

  A cercaria can survive only 48 hours in water without a mammalian host. When it finds a person, it drives into the skin using its suckers, protein-dissolving enzymes, and the movements of its tail. It then loses the tail and becomes a schistosomula. Carried along the veins, schistosomulae pass through the heart and lungs and reach the portal venous system of the liver. There they mature into adults with two separate sexes. A male and female pair up, leave the liver, and settle in the veins of the intestines or the bladder to produce eggs.

  Each species chooses its own spot. S. japonicum favors the superior mesenteric veins, while S. mansoni favors the inferior ones. S. haematobium settles in the venous plexus around the bladder. S. intercalatum and S. guineensis occupy the inferior mesenteric plexus, lower in the bowel than S. mansoni.

  Adult schistosomes live an average of 3-5 years, yet their eggs can survive for more than 30 years after infection. Transmission normally happens only where the right snails are native. Even so, a man in Germany once caught the disease from an infected snail in his aquarium.

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• 3. Rash and Fever

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  Within 12 hours of infection, the skin where larvae entered can start to itch. This reaction is called cercarial dermatitis, or swimmer's itch. In a person never exposed before, the rash is usually mild, with a prickling feeling that fades by itself. Someone infected previously mounts a stronger immune response, so the rash arrives faster and looks worse. Itchy red raised spots appear, and some turn into fluid-filled blisters. The round bumps are typically one to three centimeters across.

  Tourists and migrants react more often than local residents, because people in affected areas have usually been exposed many times. The rash can appear anywhere between a few hours and a week after exposure. It normally clears on its own in around 7-10 days, and it can resemble scabies. Scratching risks a bacterial skin infection. Corticosteroid cream, cool compresses, a bath with Epsom salts or baking soda, and oral antihistamines can ease the itch.

  Cercariae from animal trematodes that often infect birds can cause a nearly identical rash. Cercarial dermatitis is not contagious and cannot pass from person to person.

  Katayama fever arrives around 2-8 weeks after infection, long after the rash has gone. Its name comes from the Katayama district of Hiroshima Prefecture in Japan, where schistosomiasis was once endemic. The fever is a whole-body reaction to larvae moving through the bloodstream and lungs to the liver, and to substances released by eggs. Patients may have fever, chills, muscle aches, a dry cough, headache, abdominal pain, bloody diarrhea, hives, or swollen lymph nodes. The liver and spleen can enlarge. Most cases resolve within 2-8 weeks, though a small proportion of patients are left with persistent weight loss, diarrhea, and abdominal pain.

  Many infected people never notice any of this, and the eggs the worms lay are the next source of trouble.

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• 4. Gut and Liver

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  Between 10 and 50 percent of people living where S. mansoni and S. japonicum are endemic develop intestinal schistosomiasis. The adult worms cause less harm than the eggs they lay. Eggs secrete enzymes that help them tunnel toward the intestine or bladder to be shed, but many get stuck in tissue. Trapped eggs provoke granulomas, nodules of immune cells that bring chronic inflammation, fibrosis, and tissue destruction. The miracidia inside the eggs keep releasing inflammatory antigens for about 6-8 weeks before they die. Because the worms keep laying, the number of trapped eggs keeps rising until the worms are eliminated.

  In the large bowel and rectum, trapped eggs cause abdominal pain, loss of appetite, mucous diarrhea, and blood in the stool. The small bowel is rarely involved. Severe disease brings polyps, ulcers, iron-deficiency anemia, and narrowing of the colon or rectum, and an infected person may develop what looks like a potbelly. Light infections may go unrecognized. In Sub-Saharan Africa, where S. mansoni overlaps with high HIV prevalence, gastrointestinal schistosomiasis has been linked to increased HIV transmission.

  Liver fibrosis develops in 4 to 8 percent of people with chronic infection, mainly after long and heavy infection. Children and adolescents first show an inflammatory phase, in which eggs trapped in the liver create numerous granulomas. Liver function stays normal, yet the liver and spleen swell. In severe cases they can reach the level of the belly button or even the pelvis.

  Young and middle-aged adults may later develop the fibrotic phase, as collagen builds up around the portal vessels in a pattern called Symmer's pipe stem fibrosis. Unlike cirrhosis, it does not damage liver function or architecture. For S. mansoni it usually takes around 5-15 years to develop, and it can take less time for S. japonicum. Co-infection with hepatitis C is associated with faster liver deterioration and worse outcomes.

  The scarring squeezes the portal vein and raises pressure in the vessels that drain the gut. The spleen enlarges, fluid collects in the abdomen, and swollen veins in the esophagus, called esophageal varices, can tear and bleed profusely.

  In pulmonary schistosomiasis, the new connections that high pressure opens between the liver circulation and the rest of the body let eggs reach the lungs. Eggs lodged near the smallest lung capillaries cause granulomatous inflammation and then fibrosis. Pressure rises in the lung circulation and strains the right side of the heart. Patients may have shortness of breath, chest pain, lethargy, and fainting during exertion.

  That same detour also gives eggs a path to the spinal cord and the brain.

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• 5. Bladder and Brain

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  S. haematobium can produce up to 3000 eggs per day, and up to 50 percent of them may become trapped in the tissue around the bladder and ureters. Inflammation, polyps, and ulcers follow. Blood in the urine appears 10 to 12 weeks after infection and is the most common symptom, usually seen at the end of the stream. Other signs include painful and frequent urination, protein in the urine, secondary urinary and kidney infections, and calcification of the bladder wall. Over time, fibrosis can block the urinary tract, swell the kidney, and cause kidney failure.

  The International Agency for Research on Cancer classes S. haematobium as a group 1 biological carcinogen. Bladder cancer diagnosis and mortality are generally elevated in affected areas, and efforts to control schistosomiasis in Egypt have lowered the bladder cancer rate. The risk appears especially high in male smokers. One suggested reason is that chronic irritation of the bladder lining exposes it to carcinogens from smoking.

  In women, genital lesions of the cervix, vagina, or vulva can raise rates of HIV transmission. Lesions in the fallopian tubes or ovaries may cause infertility. In men, there can be blood in the semen. Kidney function is unaffected in many cases, and the lesions are reversible when treatment eliminates the worms.

  Communities in China affected by S. japonicum have rates of seizures eight times higher than baseline. Eggs and worms that reach the brain or spinal cord through the circulation set off inflammation and granulomas, which can leave irreversible scarring without treatment. When many eggs cluster in one area, ringed by large granulomas, they act like a mass. The result can be headache, weakness on one side of the body, altered mental status, vertigo, visual problems, seizures, and unsteady movement.

  In the spinal cord, granulomas from S. mansoni and S. haematobium eggs can cause transverse myelitis. This inflammation brings paralysis of the legs, loss of bowel or urinary control, and loss of sensation below the lesion. Doctors give corticosteroids to prevent permanent neurological damage, sometimes adding anticonvulsants to stop seizures, and they give the corticosteroids before praziquantel.

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• 6. Finding the Eggs

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  Eggs of S. mansoni measure about 140 by 60 micrometers and carry a lateral spine, which makes them recognizable under a microscope. Diagnosis is confirmed by finding such eggs, in stool when S. mansoni or S. japonicum is suspected and in urine when S. haematobium is suspected. Eggs pass intermittently or in small numbers, so repeated examinations improve detection. The Kato-Katz technique measures egg output semiquantitatively from 20 to 50 milligrams of feces. For S. haematobium, urine collected between noon and 3 PM is recommended. When stool and urine are negative, a biopsy of the rectum, bladder, or liver may still reveal eggs.

  A microscope test costs about US$0.40, while PCR costs about US$7 per test as of 2019. PCR is accurate and rapid, but the equipment and expertise it needs are scarce where the disease is common. Loop-mediated isothermal amplification, a cheaper method, was under study and not commercially available as of 2019. In 2005, a team led by Russell Stothard of the Natural History Museum of London tested a novel handheld microscope in Uganda, working with the Schistosomiasis Control Initiative.

  At the US Centers for Disease Control and Prevention, serum is tested by FAST-ELISA using S. mansoni adult microsomal antigen. Sensitivity is 99 percent for S. mansoni, 95 percent for S. haematobium, and under 50 percent for S. japonicum. Specificity is 99 percent. Because sensitivity drops for the other species, immunoblots matched to the patient's travel history are also run. A positive antibody result shows only that infection occurred at some time. It says nothing about current illness, worm burden, egg production, or prognosis.

  A urine dip-stick can screen a community for blood in the urine, and urine reagent strips confirming microhematuria identify active infection in endemic areas more accurately than circulating antigen tests. A stool guaiac test can check for blood in the stool. In travelers and migrants, a high eosinophil count in a blood test can suggest acute infection.

  Imaging shows the damage. A pelvic X-ray can reveal calcification of the bladder in chronic urinary disease, and ultrasound checks the liver and spleen. CT of the liver can show calcification linked to S. japonicum, and MRI evaluates the central nervous system. In rare cases, PET/CT scans have helped diagnose the disease, because inflammation around the eggs raises the metabolic rate of nearby tissue.

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• 7. Dams and Drugs

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  From the 1950s onward, vast dams and irrigation schemes were built across the tropics, and schistosomiasis surged along with them. United Nations documents since the 1950s had described how to design irrigation so that snails struggle to colonize it and people have less contact with the water. The designers were unaware of the guidance. Egypt shows the pattern, with the disease endemic and made worse by dam and irrigation projects along the Nile.

  The large migratory prawn Macrobrachium eats snails, and dams appear to have reduced its numbers. After fourteen large dams were built, schistosomiasis rose more in the historical habitats of native prawns than elsewhere. At the Diama Dam on the Senegal River, dated to 1986, restoring prawns upstream reduced both snail density and human reinfection.

  Chemical attacks on snails with molluscicides were tried in the past, but they were expensive and often reduced the snail population without eliminating it. In some places, urbanization, pollution, and the destruction of snail habitat lowered exposure and new infections. A 2014 review found tentative evidence that clean water and sanitation reduce infection.

  China's national strategy has shifted three times since the mid-1950s. Transmission control ran until the early 1980s. From the mid-1980s to 2003, the focus was morbidity control, with synchronized chemotherapy for humans and bovines. In 2004 the new integrated strategy replaced bovines with machines, banned grazing cattle on grasslands, improved sanitation, and put fecal-matter containers on boats. It added praziquantel, snail control, and health education. A 2018 review found it cut the risk of S. japonicum infection by 3-4 times compared with the conventional strategy.

  Praziquantel arrived in the 1980s. Until then, antimony potassium tartrate remained the treatment of choice. Praziquantel costs less per treatment, and oxamniquine does not work against S. haematobium. Praziquantel can be used safely in pregnant women and young children, and a single oral dose each year can control the disease in a community. It kills adult worms but not eggs or immature worms. Live eggs can still be excreted for weeks, so stool or urine should be tested again around 4-6 weeks later and treatment repeated if needed.

  Timing matters in acute illness. Praziquantel does not work on young schistosomulae, and treating too early can worsen symptoms, sometimes dangerously. Doctors use corticosteroids such as prednisone to calm the reaction. Oxamniquine, given once, is more effective against young worms than praziquantel but only for S. mansoni. Mefloquine, long used against malaria, was recognized in 2008-2009 as effective against schistosomes.

  The World Health Organization sets thresholds by the share of village children with blood in their urine. Above 50 percent, everyone in the village is treated. Between 20 and 50 percent, only school-age children are treated. Below 20 percent, mass treatment is not carried out. In 2019-44.5 percent of people with schistosomiasis were treated globally. Among school-aged children needing preventive treatment, 67.2 percent received it.

  In Egypt, from the late 1950s through the early 1980s, infected villagers received repeated injections of tartar emetic. Epidemiological evidence suggests the campaign unintentionally spread hepatitis C through unclean needles. Egypt has the world's highest hepatitis C infection rate, and regional rates there closely track the timing and intensity of that campaign.

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• 8. Old Disease, Open Questions

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  In 2010, approximately 238 million people were infected, and 85 percent of them lived in Africa. An estimated 600 to 700 million people live where the parasite is common, and in 2012 some 249 million needed treatment. Among tropical parasitic diseases, only malaria ranks higher in economic and public health importance. S. haematobium alone infects over 112 million people annually in Sub-Saharan Africa. It causes 32 million cases of painful urination, 10 million of kidney swelling, and 150,000 deaths a year from kidney failure, making it the world's deadliest schistosome.

  Estimates of deaths vary widely. The Global Burden of Disease Study issued in 2010 counted 12,000 direct deaths, while the World Health Organization in 2014 estimated more than 200,000 related deaths. The 2021 edition of the study counted 12,858. Another 20 million people suffer severe consequences.

  The burden falls on those who spend time in the water. Children play in it, and in many affected areas a large proportion of children under 14 are infected. In children the disease may stunt growth and cause learning difficulties. Women face exposure through washing clothes and fetching water, and farmers and fishermen work in it daily.

  Human skeletal remains from northern Syria, dated 5800-4000 BC, contained a spined schistosome egg in pelvic sediment. The earliest known case, found in 2014, belonged to a child who lived 6,200 years ago. Some researchers place the cradle of the schistosomes in the region of the African Great Lakes. It is believed the disease reached Egypt during the fifth dynasty, ca. 2494-2345 BC, with imported monkeys and slaves. In the Greco-Roman Period it was a common cause of death for Egyptians.

  The name bilharzia honors Theodor Bilharz, a German physician working in Egypt, who first described the cause of urinary schistosomiasis in 1851. The Brazilian parasitologist Pirajá da Silva described the entire disease cycle in 1908. The genus name Schistosoma means 'split body'. By the early 20th century in Egypt, blood in the urine was seen as a male version of menstruation and treated as a rite of passage for boys.

  A vaccine candidate against S. haematobium called Bilhvax went through a phase 3 trial among children in Senegal. The results, reported in 2018, showed it was ineffective despite provoking some immune response. Researchers using CRISPR gene editing reduced the symptoms of the disease in an animal model.

  Researchers at Tufts University used thromboelastography and found that mouse blood incubated with adult worms for one hour clotted like the blood of patients with hemophilia or on anticoagulant drugs. That suggests schistosomes may have anticoagulant properties, and blocking them could become a treatment.

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