Understanding Schistosomiasis: A Global Health Threat

1. Digeneans: All life cycles involve a mollusc and a vertebrate All life cycles are similar but different All life cycles are a variation of one theme. Adult-egg-miracidium-[black box of sprorocyst/rediae] Cercariae leave snail (usually): 1) penetrate host (definitive or intermediate) 2) encyst on vegetation

2. Among human parasitic diseases, schistosomiasis (sometimes called bilharziasis) ranks second behind malaria in terms of socio-economic and public health importance in tropical and subtropical areas. The disease is endemic in 74 developing countries, infecting more than 200 million people in rural agricultural and peri-urban areas. Of these, 20 million suffer severe consequences from the disease and 120 million are symptomatic. In many areas, schistosomiasis infects a large proportion of under-14 children. An estimated 500-600 million people worldwide are at risk from the disease Globally, about 120 million of the 200 million infected people are estimated to be symptomatic, and 20 million are thought to suffer severe consequences of the infection. Yearly, 20,000 deaths are estimated to be associated with schistosomiasis. This mortality is mostly due to bladder cancer or renal failure associated with urinary schistosomiasis and to liver fibrosis and portal hypertension associated with intestinal schistosomiasis.

3. Biogeography The major forms of human schistosomiasis are caused by five species of water-borne flatworm, or blood flukes, called schistosomes: Schistosoma mansoni causes intestinal schistosomiasis and is prevalent in 52 countries and territories of Africa, Caribbean, the Eastern Mediterranean and South America Schistosoma japonicum/Schistosoma mekongi cause intestinal schistosomiasis and are prevalent in 7 African countries and the Pacific region Schistosoma intercalatum is found in ten African countries Schistosoma haematobium causes urinary schistosomiasis and affects 54 countries in Africa and the Eastern Mediterranean.

5. In the case schistosomiasis, the adult worms reside in the blood vessels lining the liver, intestine, or bladder . Only about a half of the eggs are excreted in the feces (intestinal schistosomiasis), or in the urine (urinary schistosomiasis). The rest stay in the body, damaging other vital organs. It is the eggs and not the worm itself which cause damage to the intestines, the bladder and other organs.

6. The miracidium swim through the water until they come in contact with a suitable snail host (suitability being determined by the species of both the parasite and the snail). S. mansoni only infect snails of the genus Biomphalaria. S. haematobium infect species of Bulinus. S. japonicum are found in Oncomelania sp.

7. Intermediate hosts The life cycle within the snail is the same for all schistosome species. The miracidium actively searches out its specific snail host, penetrates snail tissue, changes into a mother sporocyst and gives rise to a daughter sporocyst. This sporocyst migrates to the digestive gland or reproductive organ, where further multiplication occurs and a new larva, the cercariae (the stage infective to man), is produced. It takes approximately four weeks at 26-28 OC for the miracidium to produce cercariae within the snail body. After maturing, the cercariae emerge from the snail and enter the surrounding water. One miracidium may end up generating several thousand cercariae. Freshwater snails are considered the intermediate hosts of schistosome infection, rather than vectors, because transferring the infection requires no physical contact between man and snail. The relationship between parasite and snail first intermediate host is very specific

8. Once the cercariae penetrate the skin of their host, they burrow into the peripheral capillary bed of the blood circulatory system or enter the lymphatic system. Worms reach the right side of the heart and then enter the pulmonary capillaries of the lungs During this process, 3 significant morphological changes occur in the cercariae: the tail is lost, the surface coat is lost, and contents of the penetration gland is spent. The transformed cercaria is called a schistosomule After about a week, the schistosomules move through the pulmonary vein to the left side of the heart and then into the systemic circulation About 3 weeks post penetration the worms reach the hepatic portal veins (S. mansoni), veins of the small intestine (S. japonicum), or those of the urinary bladder (S. haematobium) where they reach sexual maturity and mate

9. S. mansoni and S. japonicum reside within the blood vessels that line the liver/intestine, while S. haematobium live in the vessels of the bladder. Paired male and female adult worms. The female is the darker, curled worm within the male's gynacophoric canal. The females then begin to produce eggs about 25 to 30 days after host infection. Females are able to produce up to 3,000 eggs per day for 3 to 8 years.

10. The mouth of the adult schistosome is surrounded by an oral sucker; a ventral sucker is located immediately posterior to the level of bifurcation of the gut No pharnyx is present; however, here is an esophagus with prominent esophageal glands

11. Life Cycle • Female deposits eggs • The egg must penetrate the venuole endothelium and traverse the intervening tissues and the mucosal lining before entering the lumen of the gut or the bladder to escape to the outside • Eggs probably pass through tissues via hydrolytic secretions emitted through the porous shell; only about 1/3-1/2 of the eggs produced reach the exterior, with the remaining eggs being trapped in the urinary bladder, intestinal walls or swept back by the blood flow to become lodged in ectopic sites (liver or spleen) • After reaching the lumen, the egg passes out in either feces or urine • IF THIS WERE THE END OF THE STORY THE LECTURE WOULD BE OVER! • Some eggs are trapped in body tissues. Immune reactions to eggs lodged in tissues are the cause of disease. 

12. Pathology • 1. The migration phase (from penetration to egg production) • There are often no symptoms • Characterized by toxic reactions and pulmonary congestion, fever • This phase may last 4-10 weeks, during which the worms migrate from the lungs to the final destination where they reach sexual maturity and mate • 2. The acute phase (begins at egg production) • This phase is considerably longer, lasting 2 months to several years • Symptoms such as blood in stools (S. mansoni and S. japonicum) and hematuria (S. hematobium) are caused by passage of eggs through the intestinal and urinary bladder walls • 3. The chronic phase • Usually there is mild, chronic bloody diarrhea, with mild abdominal pain and lethargy, or with S. haematobium there is pain during urination. Also characterized by severe intestinal, renal, and hepatic pathology, caused by the reaction of the host to schistosome eggs. • Enlargement of the liver (=liver fibrosis) and spleen is a common symptom of advanced schistosomiasis. Eggs trapped in the walls of the intestine and urinary bladder as well as ectopic regions, notably the liver and the spleen, elicit inflammatory reactions resulting from leucocystic and fibroblastic infiltration and producing cirrhosis, anemia, etc

13. Pre-patent period skin invasion, maturation and migration of worms- rash, itching, allergic reaction, diarrhea, fever, inflammation of intestinal tissues Egg deposition blood/mucous in feces or urine, fever (immune response to eggs) Tissue proliferation, repair, degenerative effects eggs trapped in tissues, WBC surround eggs, lay down connective tissue to isolate eggs- granuloma. So much tissue may be layed down over time that organs lose elasticity, vessels become blocked, eggs transported to liver, same reaction, liver function affected, progressive damage S. hematobium: eggs can reach 200-800 eggs/ml of urine

14. In urinary schistosomiasis (due to S. haematobium) damage to the urinary tract is revealed by blood in the urine. Urination becomes painful and is accompanied by progressive damage to the bladder, ureters and then the kidneys. Bladder cancer is common in advanced cases.  In intestinal schistosomiasis (infection with S. mansoni, S. japonicum, S. mekongi) disease is slower to develop. There is progressive enlargement of the liver and spleen, intestinal damage due to fibrotic lesions around eggs lodged in these tissues, and hypertension of the abdominal blood vessels. Bleeding from these vessels leads to blood in stools, and can be fatal. Sufferers become seriously weakened by the disease and, in some cases, the functioning of organs such as spleen and kidneys becomes impaired. Death is mostly due to bladder cancer associated with urinary schistosomiasis and to bleeding from varicose veins in the oesopahagus associated with intestinal schistosomiasis. Children are especially vulnerable to infection, which develops into chronic disease if not treated.

15. Eventually, a granuloma forms around each egg or cluster of eggs; the result of leukocyte infiltration and secretion of fibroblast growth factors • Small abscesses, accompanied by occlusion of small blood vessels, lead to necrosis and ulceration Schistosoma egg in the liver : granuloma formation Intestinal schistosomiasis: eggs in the wall of the gut

16. The morbidity associated with schistosomiasis results from the mechanical and toxic irritation caused by eggs lodged in blood vessels and by granulomas, which are localized tissue reactions to eggs. As the immune system recognizes the egg as a foreign body and tries to destroy it, scar tissue develops around the egg, forming a granuloma. There is a direct relationship between the number of eggs in tissues and the severity of symptoms. The numbers of eggs are, in turn, directly proportional to the total worm burden and the duration of the infection. The type of pathology experienced by an infected individual is also a function of the location of the egg-producing worms, which varies with the species of schistosome. In endemic areas, where re-infection is common, repeated penetration of the intestinal and urinary bladder walls by migrating eggs results in extensive scar tissue formation, which impedes the normal functioning of the organs For instance, S. haematobium infections alter absorptive properties of the urinary bladder wall, predisposing it to malignancy Because formation of scar tissue also blocks the migration of eggs through infected organs, more eggs are swept back to other sites, producing organ enlargement (e.g. the liver and spleen)

17. A Big risk class is in children under the age of 14, who make up a large portion of the population infected. Perfomance in children is also detrimentally affected: school grades and growth patterns are proven to be hindered by the disease.

18. Treatment • No reliable prophylactic regimen is presently available other than the observance of proper sanitation procedures, avoidance of cercariae-infested waters, and the prevention of water contamination by human excreta • There are a number of chemotherapeutic agents on the market, many of which have toxic side effects- and for specific regions MAY NOT BE A GOOD IDEA. • According to WHO, the key to future schistosomiasis control lies in a 4-pronged attack: • - population-based chemotherapy, repeated drug administration to infected individuals • - use of molluscicides • - introduction of biological controls, such as carnivorous snails and fish • - education of the population

19. Laboratory Diagnosis:Microscopic identification of eggs in stool or urine is the most practical method for diagnosis.  Stool examination should be performed when infection with S. mansoni or S. japonicum is suspected, and urine examination should be performed if S. haematobium is suspected. Since eggs may be passed intermittently or in small amounts, their detection will be enhanced by repeated examinations and/or concentration procedures 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.

20. Immunity • A wide range of immune responses, both humoral and cell mediated • Such responses can be correlated with several parasitic stages in the human host • 1. Skin penetration stage, is characterized by a response to the penetrating cercaria’s glycocalyx and penetration gland secretions, both released in the host’s tissues • 2. Early development stage produces 2 responses: • A. One is caused by tegumental changes of the migrating schistosomule • B. The other is a response to immunogens released from either migrating or trapped eggs • The immunogens are macromolecules that diffuse through micropores in the eggshell • Some of these macromolecules facilitate migration of eggs through the tissues • They also elicit a granulomatous response to eggs trapped in the tissues, causing pronounced pathological changes • The third, or adult worm, stage is a response to immunogens released from the adult worm’s intestine, tegument and excretory system

21. If the adult worms live freely in the body- why do we not recognize and kill the parasites???? • - Absorb host antigens from the host serum onto body • Produce antigens very similar to those of the host • Not recognized as non-self • Concomitant immunity

22. Calculation: If in an endemic area 100,000 snails in waters around a village 10% prevalence= 10,000 infected snails 10,000 snails X 1,000 cercariae/snail/day=10 million cercariae/day Cercariae shed often to coincide with the presence of hosts Cercariae can attach with secretions produced in postacetabular glands, penetrate skin, reach sub-epithelial layers within 30 minutes, drop tails, etc=schistosomules S. mansoni cercariae exit snails 11 AM - 2 PM. S. rodhaini cercariae exit snails 11 PM - 3 AM S. douthitti cercariae exit snails 11 PM -3 AM

23. Frequency Distributions

24. Overdispersion Most hosts have few or no parasites- some hosts have very many parasites. • If this is the case with Shistosomiasis how should we approach control programs in endemic regions? • Give drugs to all members of community • Give drugs to teenage boys? • Give drugs to school age children? • Give drugs only to those with >X eggs/ml urine or gm/feces? Concomitant immunity

25. Schistosomiasis, as with many communicable diseases, is a result of inequity and poverty. People get infected because they do not have access to safe, potable water, and maintain transmission because of the absence of proper sanitation systems. Infection is acquired during routine domestic, agricultural or occupational duties.  Development, both planned and unplanned, has resulted in a number of changes in the epidemiology of the disease that threaten to expand the infected population, reduce productivity and minimize development gains. Water development schemes, including dam building and irrigation systems, have created new breeding sites for snails. Intensive agriculture has encouraged people to migrate to urban and peri-urban areas that are ill-prepared to meet their needs for sanitation and water. In these areas, snail-infested streams and canals are often the most convenient water sources. New agricultural systems that emphasize irrigation, double cropping and other intensive cultivation practices have increased farmers' exposure to infection.

26. Swimmers Itch • An interesting aspect of schistosome biology concerns cercarial dermatitis or swimmer’s itch • The condition is caused when cercariae of blood flukes that normally parasitize aquatic birds and mammals penetrate the human skin, sensitizing the areas of attack and causing pustules and an itchy rash • Since humans are not suitable definitive hosts for these flukes, the cercariae do not normally enter the blood stream and mature • Instead, after penetrating the skin, they are destroyed by the victim’s immune response • Allergenic material released from dead and dying cercariae produce a localized inflammatory reaction

27. EDMONTON ‑ Matt Farnholtz's nightmare began when he found his command of Spanish mysteriously slipping in Central America. It wouldn't end until tropical medicine experts in Canada got a good look at his brain and reviewed his history of adventurous travel. What they found would make even the most hardened Third World wanderer more cautious in the future. The 25‑year old could not remember Spanish words he had already mastered. Soon, he was also experiencing persistent headaches, abnormal sensations in his right arm and leg. plus nausea and vomiting. The UBC student flew back to Canada but the doctors had difficulty finding a link between the tropical diseases in Costa Rica the peculiar symptoms he was exhibiting. A CAT scan and an MRI revealed a huge mass on the brain. Doctors first thought it was a tropical disease, then a cyst, and finally a brain tumour. Doctors performed a biopsy and recovered inflammatory cells, indicating significant swelling but not what was causing it. Steroids reduced the swelling but each time they tapered off the dosage to avoid side‑effects his condition grew worse. " The doctors told me I had a brain tumour and I was going to die. The next day surgeons opened up his skull and discovered huge deposits of eggs. An infectious disease lab technician identified helminth eggs. "I'm just waking up and my mom says, 'It's really good news. You've, got a worm in your brain.“ Amazingly the lab expert recognized the eggs immediately as signs of schistosoma mekongi. a parasite found in the Mekong River far from Costa rica. The young man and two friends had traveled to Laos two years earlier, they ignored the advice in the Lonely Planet guidebook and went swimming in the Mekong River. Big Mistake. 200 million people are infected worldwide with bilharzias, 1 million die/yr. The centimeter-long worms live in the bladder or bowel wall, releasing 100’s of eggs/day for 20-30 years. The eggs are generally passed from the body but cause damage to tissues which ultimately become inflamed and fail to function. For some reason, a parasite pair wandered off course and ended up in a blood vessel in his brain. The deposit of eggs built up instead of passing from the body. Fortunately, he received a drug which causes the worms and eggs to disintegrate. He was also given corticosteroids for a few months to reduce the inflammation in his brain. The result? Complete recovery. I’m very lucky,” he says. “People get this all the time in the Third World and they just die. If I was a local I’d be dead now. I’m concerned it might have been fatal or at least caused serious brain injury.” After the diagnosis, he his travel buddies, in England and Switerzland. Both tested positive for more conventional forms of bilharzias and were successfully treated.