Schistosoma species (Schistosomiasis)
Authors: Michael H. Hsieh, M.D., Ph.D.
Previous Author (First Edition, 2002): Adel A. F. Mahmoud, M.D., Ph.D.
Parasitology
Human infection with worms of the Schistosoma species is responsible for significant morbidity and mortality worldwide (15). Five clinically important species are responsible for the bulk of human infections. These are Schistosoma haematobium, S. mansoni, S. japonicum, S. intercalatum and S. mekongi. Humans can also be infected with animal or avian schistosomes but this results in no or little morbidity. Adult schistosomes parasitize specific locations of the venous system: the pelvic plexus (S. haematobium) and mesenteric veins (other species). Upon maturation, the female worms deposit their ova intravascularly. Some of the eggs pass from the lumen of veins to that of nearby visci to be excreted with urine or feces. Schistosome eggs hatch upon reaching fresh water in the environment releasing miracidia that seek and infect specific intermediate snail host. The next stage, cercariae, are released from infected snails; they are capable of penetrating intact human skin. Upon entering the dermis, cercariae change into the schistosomula stage and migrate in the host tissues via the lungs and liver to reach their final habitat.
Epidemiology
Schistosoma haematobium is found in Africa and the Middle East; S. mansoni occurs in Africa and Brazil; S. japonicum in China and the Philippines; S. intercalatum in West and Central Africa; and S. mekongi in Southeast Asia. In the United States, although schistosomiasis is seen in immigrants from endemic countries, transmission does not occur as there is no appropriate snail intermediate host and there is sanitary disposal of feces and urine (the biofluids which contain excreted schistosome eggs).
Clinical Manifestations
Three distinct clinical conditions occur in schistosomiasis and are related to specific stages of the parasite. Cercarial dermatitis occurs following exposure. The papular pruritic rash, also called swimmers itch, is more prominent in infection with avian species. Acute schistosomiasis or Katayama fever coincides with maturation of adult worms and the beginning of oviposition. It is a serum-like syndrome and occurs in heavy infections of infection-naive individuals, particularly with S. japonicum. Patients are febrile with flu-like symptoms including cough and headache. They often develop hepatosplenomegaly, lymphadenopathy and prominent peripheral eosinophilia. Chronic schistosomiasis occurs because of retention of eggs in host tissues, with resultant granuloma formation. S. japonicum and S. mansoni infections result in chronic intestinal and hepatic dysfunction. Fatigue, colicky abdominal pain, diarrhea, and anemia due to blood loss from intestinal ulcerations occur with intestinal schistosomiasis. The eggs in the portal circulation may cause presinusoidal blockage of the portal blood vessels resulting in portal hypertension. Chronic schistosomiasis often presents with hepatosplenomegaly and may progress to decompensated liver disease. The eggs may also enter the lung and cause granulomatous obstruction of the pulmonary blood vessels, resulting in cor pulmonale. S. haematobium infections involve the ureters and bladder and other pelvic organs. These patients present initially with hematuria and dysuria and later, obstructive uropathy and uremia. Squamous cell carcinoma of the bladder is known to occur in patients with chronic S. haematobium infections. Central nervous system involvement by schistosomiasis occurs infrequently. S. haematobium and S. mansoni most commonly affect the spinal cord, while S. japonicum affects the brain.
Laboratory Diagnosis
Diagnosis of human infection with any of the schistosome species is based on obtaining accurate geographic history and experiences that may result in exposure. Thorough clinical and laboratory evaluation is a must. Definitive diagnosis depends on demonstrating schistosome eggs in urine or feces in rare circumstances, tissue samples (e.g. rectal biopsies). Recent advances in serological testing for schistosomes make these assays a valuable step in diagnosis. Most of the available tests evaluate antibody responses but several newer methods for quantification of schistosome antigens in serum or urine samples are being introduced (10). Once diagnosis is made, assessment of the extent of clinical disease is imperative. This may include ultrasonographic examination of the urinary tract and liver and portal circulation.
Pathogenesis
The host cell-mediated immunopathological reaction to retained eggs results in granuloma formation and an array of immunological responses that are responsible for induction and regulation of the lesions of schistosomiasis. For S. japonicum and S. mansoni, egg deposition occurs in the intestine and the liver to produce intestinal and hepatic fibrosis, whereas for S. haematobium egg deposition occurs primarily in the bladder to produce fibrosis leading to obstructive uropathy. The host granulomatous response in schistosomiasis involves a complex set of T cell dependent responses that include prominent T helper 2 components. Cytokines like tumor necrosis factor and interleukin-12 are also involved in granuloma formation.
SUSCEPTIBILITY IN VITRO AND IN VIVO
Attempts to develop in vitro systems to examine the effect of antischistosomal agents on the different stages of the life cycle of the helminth have met mixed success(3). The impact of chemotherapy on adult worms in vitro was evaluated visually under dissecting microscope. Parameters such as wiggling and muscle contracture were used as well as change in surface membrane. The impact on cercariae and schistosomula may be evaluated based on morphology of the organisms, their ability to exclude vital dyes and release of 51Cr (schistosomula). None of these platforms have played a major role in evaluation of the parasite drug susceptibility or resistance. Indeed, most studies of efficacy are performed in vivo. The end point of such studies is to calculate the survival and maturation of "input" cercariae into adult worms that are perfused from the hepatic and portal veins. Several animal species may be used including mice, hamsters and baboons. Another quantitative in vitro measure is to calculate egg production/female worms or egg viability in excreta, the so-called oogram. Finally, it is possible to assess egg antigenicity by measuring the host granulomatous response in vivo upon injection into pulmonary microvasculature of experimental animals.
ANTIPARASTIC THERAPY
The current drug of choice for treatment of all species of human schistosomes is Praziquantel (12). The drug is a pyrazinoisoquinoline derivative. It is administered orally as a single or divided doses over one day. The dose for treatment of S. haematobium, S. mansoni and S. intercalatum is 40 mg/kg body weight, while the drug is given as 60 mg/kg body weight for S. japonicum and S. mekongi; this dose is usually divided in two oral doses several hours part.
Praziquantel is readily absorbed following ingestion; maximum peripheral blood concentration is reached in 1-2 hours. The drug's half-life time in plasma is 1.5 hours; it is metabolized rapidly into hydroxylated and conjugated products which are excreted in urine mainly within 24 hours. Praziquantel is well tolerated in humans(12). Side effects are infrequent and include abdominal discomfort, headache and dizziness. These are transient side effects; other genotoxic activities have been reported (17) but its clinical significance of this is unknown.
The mechanism of action of Praziquantel on schistosomes and other helminths appear to relate to two events following its uptake by the parasites. Increased muscular activity, contracture and spastic paralysis of adult worms has been observed early while membrane changes including vacuolization and vesiculation are seen later. Less effect has been consistently observed when testing the drug on schistosomula as compared to adult worms. Experimental evidence also demonstrates hepatic shift of S. mansoni or S. japonicum from intestinal to liver vessels. The molecular basis for parasite mortality following praziquantel therapy in schistosomiasis is still unclear. Increased membrane permeability to cations, namely calcium, may be involved. A role for the host immune response in final killing of the parasites has been demonstrated in vivo (4). Whether this is due to exposure of surface antigens which may be targets for the immune response and which are unmasked with membrane changes is not known.
There are two other drugs with species-specific efficacy which may be used for treatment. Metrifonate (5), an organophosphorous compound has been used for treatment of S. haematobium infection. The drug is administered orally as 10-mg/kg-body weight, the dose may be repeated twice at two-week intervals. Oxamniquine has been used in South America (11) and Africa for treatment of S. mansoni infection. It is administered orally as 40-mg/kg-body weight; the dose should be increased to 60 mg/kg in treating infected individuals from Africa. With the introduction of praziquantel, the use of metrifonate and oxamniquine has decreased significantly.
ADJUNCTIVE THERAPY
Management of symptomatic patients with schistosomiasis can necessitate the use of agents other than anthelminthics (15). During the phase of cercarial dermatitis, specific chemotherapy has no impact on the course of disease. Alleviation of the macular papular pruritic rash may be attained by topical soothing applications. In patients with acute schistosomiasis, if their cardiopulmonary function is threatened, antischistosomal chemotherapy should be given along with resuscitative measures including management in an intensive care setting and the use of corticosteroids to limit the inflammatory response (40-60 mg prednisone daily to be tapered over one week). Patients with complications of the chronic states of schistosomiasis haematobium may need surgical intervention to correct ureteric obstruction, urinary tract stones, or squamous cell carcinoma of the bladder. For patients with any of the intestinal species, general medical management of deteriorating liver function or the accumulation of ascites because of portal hypertension may be needed. Surgical approaches to reverse portal hypertension and esophageal varices have been partially successful. Sclerosing techniques may be preferable for recurrent hematemesis from esophageal varices. Steroids also may be used along with specific chemotherapy in cases of cerebral or spinal cord schistosomiasis. Although there is no consensus on adequate dosing, currently 60-80 mg prednisone daily to be tapered over two weeks is suggested.
ENDPOINTS FOR MONITORING THERAPY
Chemotherapy for schistosomiasis aims at parasitological cure and reversal of pathological changes if possible. Parasitological cure is assessed by quantitative techniques examining egg excretion in urine or stool (7). The best-standardized technique for urine examination is filtration of a known volume via Nuclepore filters. Egg quantification in stools may be achieved by the Kato thick smear. Another parasitologic end point, which may be used for research purposes, is to assess viability of schistosome eggs by hatching or microscopic examination (oogram).
Reversal of pathological changes is a clinically relevant outcome, which may be used as endpoint (2, 6). The diagnostic procedures to be used depend on the schistosome species and the stage of disease. For example, ultrasonographic examination of the kidneys and urinary bladder is useful in assessing disease due to S. haematobium infection. Similarly, it may be used to monitor hepatic fibrosis and portal hypertension in S. japonicum or S. mansoni infection. Mass or selective population chemotherapy may be one of the appropriate community-level strategies for controlling schistosomiasis (8, 14).
VACCINES
There are currently no available vaccines against any of the species of schistosomes that infect humans. Experimental attempts have demonstrated the feasibility of the approach in laboratory animals but much more work is needed to identify potential protective antigens and evaluate their efficacy in humans (16).
ANTIPARASITIC AGENT PROPHYLAXIS
Currently, none of the available antischistosomal chemotherapeutic agents may be used for prophylaxis. Several preparations containing niclosamide and or other anticercarials have been used as topical applications prior to contact with suspected water bodies. Some effectiveness has been demonstrated but their practical use is limited to specific groups such as military troops during operations in schistosome-endemic areas.
COMMENTS
The availability of one broad-spectrum antischistosomal agent (praziquantel), which is also used against several other helminth infections raise the specter of development of resistance in the organism (1, 9, 12, 13). Indeed, several reports from endemic areas such as Egypt suggest that relative resistance may exist. The difficulties in testing and evaluating the susceptibility and sensitivity of schistosomes to chemotherapy complicate the objective assessment of these observations.
REFERENCES
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Brant SV, et al. Cercarial Dermatitis Transmitted by Exotic Marine Snail. Emerg Infect Dis 2010;16:1357-1365.
Leshem E et al. Acute Schistosomiasis Outbreak: Clinical Features and Economic Impact. Clin Infect Dis. 2008 Dec 15;47(12):1499-506.
Deresinski, S. Pulmonary Hypertension in Schistosomiasis. Clin Infect Dis 2009;49: iii.
Keiser J, et al. Efficacy and Safety of Mefloquine, Artesunate, Mefloquine-Artesunate, and Praziquantel Against Schistosoma haematobium: Randomized, Exploratory Open-Label Trial. Clin Infect Dis. 2010 May 1;50(9):1205-13.
Mege JL, Meghari S, Honstettre A, Capo C, Raoult D. The Two faces of interleukin 10 in human infectious diseases. Lancet Infectious Diseases 2006:7;557-569.
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Schistosomaspecies (Schistosomiasis)