SCHISTOSOMA SPECIES: PARASITOLOGY AND LIFE CYCLE
The schistosomes are a group of closely related flukes that inhabit the vascular system of a number of animals. Of the five species known to infect humans, S mansoni, S haematobium, and S japonicum are of primary importance. They infect 200 to 300 million persons in Africa, the Middle East, Southeast Asia, the Caribbean, and South America, and kill 1 million annually. The remaining two species are found in limited areas of West Africa (S intercalatum) and Southeast Asia (S mekongi), and are not discussed here in detail.
The adult worms can be distinguished from the hermaphroditic trematodes by the anterior location of their ventral sucker, by their cylindric bodies, and by their reproductive systems (ie, separate sexes). Adult specimens of different species are differentiated from one another only with difficulty. The 1 to 2 cm male possesses a deep ventral groove, or “schist.” Within this gynecophoral canal it carries the longer, more slender female in lifelong copulatory embrace. The schistosome life cycle (Figure 57–5) begins after mating in the hepato-portal circulation when the conjoined couple uses their suckers to ascend the mesenteric vessels against the flow of blood. Guided by unknown stimuli, S japonicum enters the superior mesenteric vein, eventually reaching the venous radicals of the small intestine and ascending colon; S mansoni and S haematobium are directed to the inferior mesenteric system. The destination of the former is the descending colon and rectum; the latter, however, passes through the hemorrhoidal plexus to the systemic venous system, ultimately coming to rest in the venous plexus of the bladder and other pelvic organs.
Life cycle of schistosomes.
✺ Separate sexes with different morphology
✺ Schistosoma japonicum—veins of small intestines
✺ Schistosoma mansoni—portal veins of colon and rectum
✺ Schistosoma haematobium—veins of bladder and pelvic organs
On reaching the submucosal venules, the worms begin to lay eggs. Each pair deposits 300 (S mansoni, S haematobium) to 3000 (S japonicum) eggs daily for the remainder of its 4- to 35-year life span. Enzymes secreted by the enclosed miracidium diffuse through the shell and digest the surrounding tissue. Ova lying immediately adjacent to the mucosal surface rupture into the lumen of the bowel (S mansoni, S japonicum) or bladder (S haematobium) and are passed to the outside in the excreta. Here, with appropriate techniques, they may be readily observed and differentiated. The eggs of S mansoni are oval, possess a sharp lateral spine, and measure 60 by 140 μm. Those of S haematobium differ primarily in the terminal location of their spine. The eggs of S japonicum, in contrast, are more nearly circular, measuring 70 by 90 μm. A minute lateral spine can be visualized only with care (Figure 57–1D–F).
Eggs deposited submucosally, rupture to lumina, and pass outside
The miracidia hatch quickly when the eggs are deposited in fresh water. On finding a snail host appropriate for their species, they invade and are transformed over 1 to 2 months into thousands of forked-tailed cercariae (Figure 57–3B). When released from the snail, these infectious larvae swim about vigorously for a few days. Cercariae coming in contact with human skin during this time attach, discard their tails, and penetrate. During a 1- to 3-day sojourn in the skin, the cercaria with three outer membrane layers develop into schistosomula with seven outer layers, a change that is thought to be critical to the survival of the parasite within the human body. These schistosomula enter small venules and find their way through the right side of the heart to the lung. After a delay of several days, the parasites enter the systemic circulation. Those surviving passage through the pulmonary and intestinal capillary beds return to the portal vein, where they mature to sexually active adults over 1 to 3 months, and find a mate of the opposite sex, thus completing the life cycle. Schistosomiasis is primarily a human condition, but may be zoonotic in exceptional circumstances, as demonstrated by the presence of S japonicum infection in cattle and water buffalo in southern China.
Eggs hatch to form miracidia, which invade snails
✺ Cercariae from snail traverse human skin, develop into schistosomula that invade vascular system
SCHISTOSOMIASIS (BLOOD FLUKE INFECTION)
The widespread distribution and extensive morbidity of schistosomiasis make it the single most important helminthic infection in the world today. Currently, approximately 200 million people—almost 1 in 30 of all humans—are infected worldwide. Of these, roughly 200 000 die annually. The continued transmission of the parasite depends on the disposal of infected human urine and excrement into fresh water, the presence of appropriate snail hosts, and the exposure of humans to water infested with cercariae. The construction of modern sanitation and water purification facilities would break this cycle but exceeds the economic resources of many endemic nations. Paradoxically, several massive land irrigation projects launched for the express purpose of speeding economic development have resulted in the dispersion of infection to previously uninvolved areas. Schistosoma mansoni, the most widespread of the blood flukes, is the only one present in the Western Hemisphere. Perhaps originally introduced during slavery, S mansoni is now found in Venezuela, Brazil, Surinam, Puerto Rico, the Dominican Republic, St. Lucia, and several other Caribbean islands.
✺ Most important helminthic infection
✺ Would be stopped by modern waste disposal
Perversely spread by new irrigation projects
Because a suitable snail host is lacking, transmission of S mansoni does not occur within the continental United States; however, nearly half a million individuals residing in the United States have acquired schistosomiasis elsewhere. Puerto Rican, Yemenite, and Southeast Asian populations are predominantly involved. In the Eastern Hemisphere, the prevalence of S mansoni infection is highest in the Nile Delta and tropical Africa. Isolated foci are also found in East and South Africa, Yemen, Saudi Arabia, and Israel.
Geographic distribution varies with species and depends on the presence of snail host
Schistosoma haematobium is largely confined to Africa and the Middle East, where its distribution overlaps that of S mansoni. Schistosoma japonicum affects the agricultural populations of several Southeast Asian countries, including China, the Philippines, and Sulawesi (it was eradicated from Japan in the 1990s). The closely related S mekongi is found in the Mekong and Mun River valleys of Vietnam, Thailand, Cambodia, and Laos.
Within the endemic areas of schistosomiasis, there are wide variations in both age-specific infection rates and worm loads. In general, both peak in the second decade of life and then decrease with advancing age. This finding has been explained in part by changes in the intensity of water exposure and in part by the gradual development of IgE-mediated immunity. Most infected patients carry fewer than 10 pairs of worms in the vascular system and, accordingly, lack clinical manifestations of disease. Individuals who develop much heavier worm loads as a result of repeated infections may experience serious morbidity or mortality.
Age-related susceptibility with peak in second decade
There are three major clinicopathologic stages in schistosomiasis. The first stage is initiated by the penetration and migration of the schistosomula. The second or intermediate stage begins with oviposition and is associated with a complex of clinical manifestations. The third or chronic stage is characterized by granuloma formation and scarring around retained eggs.
The major clinicopathologic manifestations of schistosomiasis result from the host’s cell-mediated immune response to the presence of retained eggs. Not all eggs are excreted into the environment, and those left behind in tissue serve as antigenic stimuli for our immune system, which walls them off in eosinophilic granulomas (“Splendore-Hoeppli reactions”). With time, the intensity of this reaction is muted; granulomas formed in the later stages of infection are smaller and less damaging than those formed early. The mechanisms responsible for this modulation are not fully understood. Present evidence suggests that both suppressor T-lymphocyte activity and antibody blockade are involved. The correlation in humans between human leukocyte antigen (HLA) types A1 and B5 and the development of hepatosplenomegaly suggests that the extent of the immunoregulation is influenced, at least in part, by the genetic background of the host.
✺ Major clinical disease manifestations from cell-mediated immune response to eggs
As evidenced by their prolonged survival, the adult worms are remarkably well tolerated by their hosts. In part, this tolerance may be attributable to the formation of IgG4 blocking antibodies early in the course of infection. Tolerance may also reflect the ability of the developing parasites to disguise themselves by adsorbing host molecules, including immunoglobulins, blood group glycolipids, and histocompatibility complex antigens. Nevertheless, as mentioned earlier, the prevalence and intensity of human infection begin to abate during adolescence, despite continuing exposure to infective cercariae. It has been suggested that schistosomula penetrating the skin after the primary infection are coated with specific antibodies, bound to eosinophils, and destroyed before they can reach the portal system. Although protection is not complete, a 60% to 80% kill rate is highly effective in controlling the intensity of parasitism. This condition, in which adult worms from a primary infection can survive in a host resistant to reinfection, is termed concomitant immunity. Eventually, production of blocking antibodies wanes whereas production of protective IgE antibodies active against adult worms increases, leading to a decrease in the host’s total worm population.
Blocking antibodies and adsorption of host molecules provide antigenic disguise
Concomitant immunity reduces new infections
SCHISTOSOMIASIS (BLOOD FLUKE INFECTION): CLINICAL ASPECTS
Within 24 hours of penetrating the skin, a large proportion of the schistosomula die. In S mansoni and S haematobium infections, immediate and delayed hypersensitivity to parasitic antigens results in an intensely pruritic papular skin rash, which increases in severity with repeated exposures to cercariae. As the viable schistosomula begin their migration to the liver, the rash disappears and the patient experiences fever, headache, and abdominal pain for 1 to 2 weeks.
✺ Local and systemic hypersensitivity reactions produce rash
Of note, a related condition happens in North America when certain schistosoma species adapted to aquatic birds mistakenly invade the skin of swimmers; unable to penetrate deeper into the human vascular systems, these cercariae remain trapped in the skin. The parasites die there without causing serious harm, but not before causing a localized pruritic, inflammatory reaction called cercarial dermatitis, or “swimmer’s itch.”
✺ Avian schistosomiasis common in North America
After 1 to 2 months of primary exposure, once the sexually mature adult worms begin to lay eggs (oviposition), patients with severe S mansoni or S japonicum infections may experience an acute febrile illness that bears a striking resemblance to serum sickness. This onset of oviposition leads to a state of relative egg antigen excess, with formation of soluble immune complexes that deposit in host tissues. Indeed, high levels of such complexes have been demonstrated in the peripheral blood and correlate well with the severity of illness. In addition to fever and chills, patients experience cough, urticaria, arthralgia, lymphadenopathy, splenomegaly, abdominal pain, and diarrhea. Sigmoidoscopic examination reveals an inflamed colonic mucosa and petechial hemorrhages; occasionally, patients with S japonicum infection develop clinical manifestations of encephalitis. Typically, leukocytosis, marked peripheral eosinophilia, and elevated levels of IgM, IgG, and IgE immunoglobulins are present. This symptom complex is commonly termed Katayama syndrome. It is more common and severe in visitors to endemic areas, in whom it may persist for 3 months or more. Occasionally it results in death.
✺ Prolonged febrile period with circulating immune complexes nucleated around soluble egg antigen
Intestinal inflammation and encephalitis occur acutely
Approximately one-half of all deposited eggs reach the lumen of the bowel or bladder and are shed from the body. Retained eggs induce inflammation and scarring, initiating the final and most morbid phase of schistosomiasis. Soluble antigens excreted by the eggs stimulate the formation of T-lymphocyte–mediated eosinophilic granulomas. Early in the infection, the inflammatory response is vigorous, producing lesions more than 100-fold larger than the inciting egg itself. With time, the host’s inflammatory response moderates, leading to a significant decrease in granuloma size. Fibroblasts stimulated by factors released by both retained eggs and the granulomas lay down scar tissue, rendering the earlier, granuloma-induced vascular obstruction permanent. As would be expected, the severity of tissue damage is directly related to the total number of eggs retained.
✺ Inflammatory and fibrotic reactions to retained eggs cause chronic disease
In S haematobium infection, the bladder mucosa becomes thickened, papillated, and ulcerated. Hematuria and dysuria result; repeated hemorrhages produce anemia. In severe infections, the muscular layers of the bladder are involved, with loss of bladder capacity and contractibility. Vesicoureteral reflux, ureteral obstruction, and hydronephrosis may follow. Progressive obstruction may lead to renal failure and uremia. Calcification of the bladder wall is occasionally seen, and approximately 10% of patients harbor urinary tract calculi. Secondary bacterial infections are common. Chronic Salmonella bacteriuria with recurrent bouts of bacteremia has been reported in Egypt, where squamous cell bladder carcinoma is frequently seen as a late complication of disease. Other urogenital organs may also be involved, including the spermatic cord, testes, fallopian tubes, ovaries, and vagina.
Schistosoma haematobium produces bladder lesions with hemorrhage and obstruction
Chronic urinary carriage of Salmonella may cause bacteremia
✺ Bladder squamous cell carcinoma a serious complication
Most bladder cancer originates from transitional cells; why is bladder cancer due to S haematobium different?
In S mansoni and S japonicum infections, the bowel mucosa is congested, thickened, and ulcerated. Patients experience abdominal pain, diarrhea, and blood in the stool. Eggs deposited in the larger intestinal veins may be carried by the portal blood flow back to the liver, where they lodge in the presinusoidal capillaries. The resulting inflammatory reaction leads to the development of periportal fibrosis and hepatic enlargement. The frequency and severity with which the liver is involved appear to be genetically determined and associated with the patient’s HLA type. In contrast to cirrhosis, in most cases of schistosomiasis liver function is well preserved. Infected persons who subsequently acquire hepatitis B or C viruses develop chronic active hepatitis more frequently than those without schistosomiasis. Presinusoidal obstruction of blood flow can result in portal hypertension and serious manifestations of portal obstruction. Eggs that are carried around the liver in the portosystemic collateral vessels may lodge in the small pulmonary arterioles, where they produce interstitial scarring, pulmonary hypertension, and right ventricular failure. Immune complexes shunted to the systemic circulation may induce glomerulonephritis. Occasionally, eggs may be deposited in the central nervous system, where they may cause epilepsy or paraplegia.
✺ Portal hypertension usually develops without cirrhosis
Hepatitis B or C superinfection may progress to chronic active hepatitis
Some differences between the clinical presentation of schistosomiasis mansoni and that of schistosomiasis japonicum have been noted. Manifestations of the latter disease typically occur earlier in the course of the infection and tend to be more severe. When involvement of the central nervous system develops, it is more likely to occur in the brain than in the spinal cord. On the other hand, immune complex nephropathy and recurrent Salmonella bacteremia are more commonly seen in hepatosplenic S mansoni infections. The latter phenomenon is apparently related to the ability of Salmonella to parasitize the gut and integument of the adult fluke, providing a persistent bacterial focus within the portal system of the infected patient. This focus cannot be eradicated without treatment of the schistosomal infection.
Elimination of Salmonella focus requires eradication of parasite
Definitive diagnosis of schistosomiasis requires the recovery of the characteristic eggs in urine, stool, or biopsy specimens. In S haematobium infections, eggs are most numerous in urine samples obtained at midday, especially the last drops voided. When examination of the sediment yields negative results, eggs may sometimes be recovered by filtering the urine through a fine membrane. Cystoscopy with biopsy of the bladder mucosa may be required for the diagnosis of mild infection. Eggs of S mansoni and S japonicum are passed in the stool. Concentration techniques such as formalin–ether or gravity sedimentation are necessary when the ova are scanty. Results of rectal biopsy may be positive when those of repeated stool examinations are negative.
✺ Schistosoma haematobium eggs found in urine
✺ Schistosoma mansoni and S japonicum eggs in stool and rectal biopsy
Because dead eggs may persist in tissue for a long time after the death of the adult worms, active infection is confirmed only when the eggs are shown to be viable. This may be performed by observing the eggs microscopically for movement of flame cell cilia or by hatching them in water and watching for motile miracidia to emerge. Quantitation of egg output may be useful in estimating the severity of infection and in following response to treatment.
Determination of egg viability and output useful
Conventional serologic tests detect circulating antibodies with sensitivities exceeding 90%, but cannot distinguish active from prior infection. Enzyme immunoassay (EIA)-based reagent strip (dipstick) tests, capable of detecting circulating, genus-specific, adult worm antigens in blood and urine, are rapid, simple, and sensitive. They are particularly helpful in the diagnosis of Katayama syndrome in those returning from endemic areas. Moreover, because antigen levels drop rapidly after successful therapy, these tests may prove helpful in distinguishing active from inactive disease.
EIA detection of antigens in blood and urine
Think ➱ Apply 57-1. This cancer is caused by a prolonged cycle of injury, at locations where eggs lodge in the bladder wall, or where they exit into the urine, triggering inflammation, repair, and scar. Over time, the squamous cells involved may become dysplastic or malignant; in effect, this is a cancer triggered by inflammation.
No specific therapy is available for the treatment of schistosomal dermatitis or Katayama syndrome. Antihistamines and corticosteroids may be helpful in ameliorating their more severe manifestations. The maturing organisms seem resistant to antiparasitic medications, thus no immediate postexposure prophylaxis after water exposure is possible. In the late stage of schistosomiasis, therapy is directed at interrupting egg deposition by killing or sterilizing the adult worms.
Several anthelmintic agents may be used. Praziquantel, which is active against all three species of schistosomes, is the agent of choice. Use of this drug is relatively contraindicated in early pregnancy. Unfortunately, reports suggest decreased efficacy of this single-dose oral agent in areas where it has been used in mass therapy programs; in this setting, repeat dosing is an option, although S mansoni infections acquired in such areas may be treated with oxamniquine (not available in the United States). Artemisinin derivatives have worked well in experimental settings, and may be useful in select cases; fostering Plasmodium resistance in patients coinfected with malaria is a real concern.
✺ Praziquantel is the drug of choice for schistosomiasis
✺ It kills adult worms, but not immature forms
Controlling this deadly disease has proved both difficult and expensive. Programs aimed at interrupting transmission by the provision of pure water supplies and the sanitary disposal of human feces are often beyond the economic reach of nations most seriously affected. Similarly, measures to deny snails access to newly irrigated lands are expensive. Chemical molluscicides have been effective in limited trials, but less successful when used over large areas for prolonged periods. Mass therapy of the infected human population has until recently been severely limited by the toxicity of older agents, or by unanticipated consequences, such as the unsanitary injection of tartrate emetic in Egypt, an antiparasitic drug that provided little benefit in terms of schistosomiasis but perversely transmitted Hepatitis C to thousands of patients. Praziquantel has proved to be more suitable for this purpose, albeit at the risk of selecting drug resistance. Furthermore, without other control measures, discontinuation of mass therapy can result in a rapid rebound of active disease.
Sanitary disposal of feces often limited by economic status
Molluscicides effective, but large-scale application difficult
In 2009, a report of an extensive controlled study in an area of Southeastern China that was hyperendemic for S japonicum yielded remarkable results that are most instructive. These included removal of cattle from snail-infested grasslands, providing mechanized equipment to farmers, improving sanitation of drinking water, building lavatories and latrines, providing boats with fecal matter containers, and implementing intensive health education programs. The infection rates fell dramatically in the intervention villages as compared to nonintervention areas. Thus, a multipronged approach such as this offers the best hope for lasting control.
Multipronged approach is necessary
Currently, there is intense interest in developing a vaccine suitable for human use. A vaccine made from irradiated S bovis cercariae, which was developed for cattle, appears to confer a significant degree of protection against infection. Although a similar live vaccine would not be practical for human populations, the success of the animal vaccine has provided clues to potential immunoprotective mechanisms in human schistosomiasis. Monoclonal antibodies have been used to identify a number of schistosomula and adult antigens thought to be capable of inducing protective immunity; more than a dozen antigens are now in various stages of investigation as vaccine candidates.
Vaccines under development