++
Human schistosomiasis is caused by five species of the parasitic trematode genus Schistosoma: S. mansoni, S. japonicum, S. mekongi, and S. intercalatum cause intestinal and hepatic schistosomiasis, and S. haematobium causes urogenital schistosomiasis. Infection may cause considerable morbidity in the intestines, liver, or urinary tract, and a small proportion of affected individuals die. Other schistosomes (e.g., avian species) may invade human skin but then die in subcutaneous tissue, producing only self-limiting cutaneous manifestations.
++
Human infection is initiated by penetration of intact skin with infective cercariae. These organisms, which are released from infected snails in freshwater bodies, measure ~2 mm in length and possess an anterior and a ventral sucker that attach to the skin and facilitate penetration. Once in subcutaneous tissue, cercariae transform into schistosomula, with morphologic, membrane, and immunologic changes. The cercarial outer membrane changes from a trilaminar to a heptalaminar structure that is then maintained throughout the organism’s life span in humans. This transformation is thought to be the schistosome’s main adaptive mechanism for survival in humans. Schistosomula begin their migration within 2–4 days via venous or lymphatic vessels, reaching the lungs and finally the liver parenchyma. Sexually mature worms descend into the venous system at specific anatomic locations: intestinal veins (S. mansoni, S. japonicum, S. mekongi, and S. intercalatum) and vesical and other pelvic veins (S. haematobium). After mating, adult gravid females travel against venous blood flow to small tributaries, where they deposit their ova intravascularly. Schistosome ova (Fig. 134-1) have specific morphologic features that vary with the species. Aided by enzymatic secretions through minipores in eggshells, ova move through the venous wall, traversing host tissues to reach the lumen of the intestinal or urinary tract, and are voided with stools or urine. Approximately 50% of ova are retained in host tissues locally (intestines or urinary tract) or are carried by venous blood flow to the liver and other organs. Schistosome ova that reach freshwater bodies hatch, releasing free-living miracidia that seek the snail intermediate host and undergo several cycles of asexual multiplication. Finally, infective cercariae are shed from snails to complete the transmission cycle.
++
++
Adult schistosomes are ~1–2 cm long. Males are slightly shorter than females, with flattened bodies and anteriorly curved edges forming the gynecophoral canal, in which mature adult females are usually held. Females are longer, slender, and rounded in cross-section. The precise nature of biochemical and reproductive exchanges between the two sexes is unknown, as are the regulatory mechanisms for pairing. Adult schistosomes parasitize specific sites in the host venous system. What guides adult intestinal schistosomes to branches of the superior or inferior mesenteric veins or adult S. haematobium worms to the vesical plexus is unknown. In addition, adult worms inhibit the coagulation cascade and evade the effector arms of the host immune responses by still-undetermined mechanisms. The genome of schistosomes is relatively large (~270 Mb) and is arrayed on seven pairs of autosomes and one pair of sex chromosomes. Sequencing of the S. japonicum, S. mansoni, and S. haematobium genomes has provided insight into the worms’ genomic and proteomic features, offering an opportunity to discover new drug targets and to understand the molecular basis of pathogenesis.
++
The global distribution of schistosome infection in human populations (Fig. 134-2) is dependent on both parasite and host factors. Information on prevalence and global distribution is inexact. At present, the five Schistosoma species are estimated to infect 200–300 million individuals (mostly children and young adults) in South America, the Caribbean, Africa, the Middle East, and Southeast Asia. Notably, parasite-related disease persists after active infection resolves, leaving a substantial health burden among adult populations. Thus, the overall number of humans likely to be affected by Schistosoma-related disease is now ~440 million. The total population living under conditions favoring transmission risk numbers ~700 million—a fact reflecting the global public health significance of schistosomiasis.
++
++
In endemic areas, the rate of yearly onset of new infection (incidence) is generally low. Prevalence, on the other hand, starts to be appreciable by the age of 3–4 years and builds to a maximum that varies by endemic region (up to 100%) in the 12- to 20-year age group. Prevalence then stabilizes or decreases slightly in older age groups (>40 years). Intensity of infection (as measured by fecal or urinary egg counts, which correlate with adult worm burdens in most circumstances) follows the increase in prevalence up to the age of 12–20 years and then declines markedly in older age groups. This decline may reflect acquisition of resistance or may be due to changes in water contact patterns, since older people have less exposure. Infection with schistosomes in human populations has a peculiar pattern. Most infected individuals harbor low worm burdens, and only a small proportion suffer from high-intensity infection. This pattern may be due to differences in worm infectivity or to a spectrum of genetic susceptibilities in human populations.
++
Disease due to schistosome infection is the consequence of parasitologic, host, and associated viral infections and of nutritional and environmental factors. Most disease syndromes relate to the presence of one or more of the parasite stages in humans. Disease manifestations in the populations of endemic areas correlate, in general, with intensity and duration of infection as well as with age and genetic susceptibility of the host. Overall, severe Schistosoma-specific disease manifestations are relatively rare among persons infected with any of the intestinal schistosomes. In contrast, symptoms of urogenital schistosomiasis manifest clinically in most S. haematobium–infected individuals. In addition, all forms of Schistosoma infection are associated with subclinical systemic morbidities that can significantly affect physical and cognitive performance, causing, for example, growth stunting, undernutrition, and anemia of chronic inflammation. New estimates of total morbidity due to chronic schistosomiasis indicate a significantly greater burden than was previously appreciated.
++
Schistosomiasis appears to be a cofactor in the spread and progression of HIV/AIDS in areas where both diseases are endemic. Increased emphasis should be placed on the treatment of schistosome infections in persons at risk of HIV/AIDS.
+++
PATHOGENESIS AND IMMUNITY
++
Cercarial invasion is associated with dermatitis arising from dermal and subdermal inflammatory responses, both humoral and cell-mediated. As the parasites approach sexual maturity in the liver of infected individuals and as oviposition commences, acute schistosomiasis or Katayama syndrome (a serum sickness–like illness; see “Clinical Features,” below) may occur. The associated antigen excess results in formation of soluble immune complexes, which may be deposited in several tissues, initiating multiple pathologic events. In chronic schistosomiasis, most disease manifestations are due to eggs retained in host tissues. The granulomatous response around these ova is cell-mediated and is regulated both positively and negatively by a cascade of cytokine, cellular, and humoral responses. Granuloma formation begins with recruitment of a host of inflammatory cells in response to antigens secreted by the living organism within the ova. Cells recruited initially include phagocytes, antigen-specific T cells, and eosinophils. Fibroblasts, giant cells, and B lymphocytes predominate later. Over time, these cumulative lesions reach a size many times that of parasite eggs, thus inducing organomegaly and obstruction. Immunomodulation or downregulation of host responses to schistosome eggs plays a significant role in limiting the extent of the granulomatous lesions—and consequently disease—in chronically infected experimental animals or humans. The underlying mechanisms involve another cascade of regulatory cytokines and idiotypic antibodies. Subsequent to the granulomatous response, fibrosis sets in, resulting in more permanent disease sequelae. Because schistosomiasis is also a chronic infection, the accumulation of antigen–antibody complexes results in deposits in renal glomeruli and may cause significant kidney disease.
++
The better-studied pathologic sequelae in schistosomiasis are those observed in liver disease. Ova that are carried by portal blood embolize to the liver. Because of their size (~150 × 60 μm in the case of S. mansoni), they lodge at presinusoidal sites, where granulomas are formed. These granulomas contribute to the hepatomegaly observed in infected individuals (Fig. 134-3). Schistosomal liver enlargement is also associated with certain class I and class II human leukocyte antigen (HLA) haplotypes and markers; its genetic basis appears to be polygenic. Presinusoidal portal blockage causes several hemodynamic changes, including portal hypertension and associated development of portosystemic collaterals at the esophagogastric junction and other sites. Esophageal varices are most likely to break and cause repeated episodes of hematemesis. Because changes in hepatic portal blood flow occur slowly, compensatory arterialization of the blood flow through the liver is established. Although this compensatory mechanism may be associated with certain metabolic side effects, retention of hepatocyte perfusion permits maintenance of normal liver function for several years.
++
++
The second most significant pathologic change in the liver relates to fibrosis. It is characteristically periportal (Symmers’ clay pipe–stem fibrosis) but may be diffuse. Fibrosis, when diffuse, may be seen in areas of egg deposition and granuloma formation but is also seen in distant locations such as portal tracts. Schistosomiasis results in pure fibrotic lesions in the liver; cirrhosis occurs only when other toxic factors or infectious agents (e.g., hepatitis B or C virus) are involved. Deposition of fibrotic tissue in the extracellular matrix results from the interaction of T lymphocytes with cells of the fibroblast series; several cytokines, such as interleukin (IL) 2, IL-4, IL-1, and transforming growth factor β, are known to stimulate fibrogenesis. The process may be dependent on the genetic constitution of the host. Furthermore, regulatory cytokines that can suppress T cell responses and fibrogenesis, such as IL-10, interferon γ, or IL-12, may play a role in modulating the response.
++
Although the above description focuses on granuloma formation and fibrosis of the liver, similar processes occur in urogenital schistosomiasis. Granuloma formation at the lower end of the ureters obstructs urinary flow, with subsequent development of hydroureter and hydronephrosis. Similar lesions in the urinary bladder cause the protrusion of papillomatous structures into its cavity; these may ulcerate and/or bleed. The chronic stage of infection is associated with scarring and deposition of calcium in the bladder wall. Among women, involvement of the birth canal can cause cervical or vaginal wall polyps and friability leading to contact bleeding, with an apparently increased risk of HIV transmission. Secondary infertility or subfecundity can also result from female genital schistosomiasis involving the uterus, fallopian tubes, or ovaries. Among men, S. haematobium infection can result in prostatic and testicular lesions with hematospermia. Superficial cutaneous lesions of the perineum can occur in both sexes.
++
Studies on immunity to schistosomiasis, whether innate or adaptive, have expanded our knowledge of the components of these responses and target antigens. The critical question, however, is whether humans acquire immunity to schistosomes. Epidemiologic data suggest the onset of acquired immunity during the course of infection in young adults. Curative treatment of infected populations in endemic areas is followed by differentiation in the pattern of reinfection. Some (susceptible) individuals acquire reinfection rapidly, whereas other (resistant) individuals are reinfected slowly. This difference may be explained by differences in transmission, immunologic response, or genetic susceptibility. The mechanism of acquired immunity involves antibodies, complement, and several effector cells, particularly eosinophils. Furthermore, the intensity of schistosome infection has been correlated with a region in chromosome 5. In several studies, a few protective schistosome antigens have been identified as vaccine candidates, but none has been fully evaluated in human populations to date.
++
In general, disease manifestations of schistosomiasis occur in three stages, which vary not only by species but also by intensity of infection and other host factors, such as age and genetics of the human host. During the phase of cercarial invasion, a form of dermatitis may be observed. This so-called swimmers’ itch occurs most often with S. mansoni and S. japonicum infections, manifesting 2 or 3 days after invasion as an itchy maculopapular rash on the affected areas of the skin. The condition is particularly severe when humans are exposed to avian schistosomes. This form of cercarial dermatitis is also seen around freshwater lakes in the northern United States, particularly in the spring and summer months. Cercarial dermatitis is a self-limiting clinical entity. During worm maturation and at the beginning of oviposition (i.e., 4–8 weeks after skin invasion), acute schistosomiasis or Katayama syndrome—a serum sickness–like illness with fever, generalized lymphadenopathy, and hepatosplenomegaly—may develop. Individuals with acute schistosomiasis have a high degree of peripheral-blood eosinophilia. Parasite-specific antibodies may be detected before schistosome eggs are identified in excreta.
++
Acute schistosomiasis has become an important clinical entity worldwide because of increased travel to endemic areas. Travelers are exposed to parasites while swimming or wading in freshwater bodies and upon their return present with acute manifestations. The course of acute schistosomiasis is generally benign, but central nervous system (CNS) schistosomiasis and even deaths are occasionally reported in association with heavy exposure to schistosomes among travelers and migrants.
++
The main clinical manifestations of chronic schistosomiasis are species-dependent. Intestinal species (S. mansoni, S. japonicum, S. mekongi, and S. intercalatum) cause intestinal and hepatosplenic disease as well as several manifestations associated with portal hypertension. During the intestinal phase, which may begin a few months after infection and may last for years, symptomatic patients characteristically have colicky abdominal pain, bloody diarrhea, and anemia. Patients may also report fatigue and an inability to perform daily routine functions and may show evidence of growth retardation and anemia. This more subtle form of schistosomiasis morbidity is generally underappreciated. The severity of intestinal schistosomiasis is often related to the intensity of the worm burden. The disease runs a chronic course and may result in colonic polyposis, which has been reported from some endemic areas, such as Egypt and Uganda.
++
The hepatosplenic phase of disease manifests early (during the first year of infection, particularly in children) with liver enlargement due to parasite-induced granulomatous lesions. Hepatomegaly is seen in ~15–20% of infected individuals; it correlates roughly with intensity of infection, occurs more often in children, and may be related to specific HLA haplotypes. In subsequent phases of infection, presinusoidal blockage of blood flow leads to portal hypertension and splenomegaly (Fig. 134-3). Moreover, portal hypertension may lead to varices at the lower end of the esophagus and at other sites. Patients with schistosomal liver disease may have right-upper-quadrant “dragging” pain during the hepatomegaly phase, and this pain may move to the left upper quadrant as splenomegaly progresses. Bleeding from esophageal varices may, however, be the first clinical manifestation of this phase. Patients may experience repeated bleeding but seem to tolerate its impact, because an adequate total hepatic blood flow permits normal liver function for a considerable period. In late-stage disease, typical fibrotic changes occur along with liver function deterioration and the onset of ascites, hypoalbuminemia, and defects in coagulation. Intercurrent viral infections of the liver (especially hepatitis B and C), toxic insults (excessive ethanol ingestion or exposure to organic poisons or aflatoxin), or nutritional deficiencies may well accelerate or exacerbate the deterioration of hepatic function.
++
The extent and severity of intestinal and hepatic disease in schistosomiasis mansoni and japonica have been well described. Although it was originally thought that S. japonicum might induce more severe disease manifestations because the adult worms can produce 10 times more eggs than S. mansoni, subsequent field studies have not supported this claim. Clinical observations of individuals infected with S. mekongi or S. intercalatum have been less detailed, partly because of the limited geographic distribution of these organisms.
++
The clinical manifestations of S. haematobium infection occur relatively early and involve a high percentage of infected individuals. Up to 80% of children infected with S. haematobium have dysuria, frequency, and hematuria. Hematuria may sometimes occur only at the end of voiding. Urine examination reveals blood and albumin as well as an unusually high frequency of bacterial urinary tract infections and urinary sediment cellular metaplasia. These manifestations correlate with the intensity of infection, the presence of urinary bladder granulomas, and subsequent ulceration. Along with local effects of granuloma formation in the urinary bladder, obstruction of the lower end of the ureters results in hydroureter and hydronephrosis, which may be seen in 25–50% of infected children. As infection progresses, bladder granulomas undergo fibrosis, which results in typical sandy patches visible on cystoscopy. In many endemic areas, an association between squamous cell carcinoma of the bladder and S. haematobium infection has been observed. Such malignancy is detected in a younger age group than is transitional cell carcinoma. In fact, S. haematobium has now been classified as a human carcinogen. Genital schistosomiasis (described in the previous section) is a common presenting symptom among adults of both sexes.
++
Significant disease may occur in other organs during chronic schistosomiasis. Lung and CNS disease have been documented; other sites, such as the skin and the genital organs, are less frequently affected. In pulmonary schistosomiasis, embolized eggs lodge in small arterioles, producing acute necrotizing arteriolitis and granuloma formation. During S. mansoni and S. japonicum infection, schistosome eggs reach the lungs after the development of portosystemic collateral circulation; in S. haematobium infection, ova may reach the lungs directly via connections between the vesical and systemic circulation. Subsequent fibrous tissue deposition leads to endarteritis obliterans, pulmonary hypertension, and cor pulmonale. The most common symptoms are cough, fever, and dyspnea. Cor pulmonale may be diagnosed radiologically on the basis of prominence of the right side of the heart and dilation of the pulmonary artery. Frank evidence of right-sided heart failure may be seen in late cases.
++
Although less common than pulmonary manifestations, CNS schistosomiasis is important, characteristically occurring in association with S. japonicum infection. Migratory worms deposit eggs in the brain and induce a granulomatous response. The frequency of this manifestation among infected individuals in some endemic areas (e.g., the Philippines) is calculated at 2–4%. Jacksonian epilepsy due to S. japonicum infection is the second most common cause of epilepsy in these areas. S. mansoni and S. haematobium infections have been associated with transverse myelitis. This syndrome is thought to be due to eggs traveling to the venous plexus around the spinal cord. In schistosomiasis mansoni, transverse myelitis is usually seen in the chronic stage after the development of portal hypertension and portosystemic shunts, which allow ova to travel to the spinal cord veins. This proposed sequence of events has been challenged because of a few reports of transverse myelitis occurring early in the course of S. mansoni infection. More information is needed to confirm these observations. During schistosomiasis caused by Schistosoma haematobium, ova may travel through communication between vesical and systemic veins, resulting in spinal cord disease that may be detected at any stage of infection. Pathologic study of lesions in schistosomal transverse myelitis may reveal eggs along with necrotic or granulomatous lesions. Patients usually present with acute or rapidly progressing lower-leg weakness accompanied by sphincter dysfunction.
++
Physicians in areas not endemic for schistosomiasis face considerable diagnostic challenges. In the most common clinical presentation, a traveler returns with symptoms and signs of acute syndromes of schistosomiasis—namely, cercarial dermatitis or Katayama syndrome. Central to a correct diagnosis is a thorough inquiry into the patient’s history of travel and exposure to freshwater bodies—whether slow- or fast-running—in an endemic area. Differential diagnosis of fever in returned travelers includes a spectrum of infections whose etiologies are viral (e.g., dengue fever), bacterial (e.g., enteric fever, leptospirosis), rickettsial, or protozoal (e.g., malaria). In cases of Katayama syndrome, prompt diagnosis is essential and is based on clinical presentation, high-level peripheral-blood eosinophilia, and a positive serologic assay for schistosomal antibodies. Two tests are available at the CDC: the Falcon assay screening test/enzyme-linked immunosorbent assay (FAST-ELISA) and the confirmatory enzyme-linked immunoelectrotransfer blot (EITB). Both tests are highly sensitive and ~96% specific. In some instances, examination of stool or urine for ova may yield positive results.
++
Individuals with established infection are diagnosed by a combination of geographic history, characteristic clinical presentation, and presence of schistosome ova in excreta. The diagnosis may also be established with the serologic assays mentioned above or with those that detect circulating schistosome antigens. These assays can be applied to blood, urine, or other body fluids (e.g., cerebrospinal fluid). For suspected schistosome infection, stool examination by the Kato thick smear or any other concentration method generally identifies most patients with heavy infection but does not identify all lightly infected individuals. For the latter patients, a point-of-care test to detect parasite circulating cathodic antigen in urine may prove very useful in establishing the presence of active S. mansoni infection and in monitoring the clearance of infection after treatment. For S. haematobium, urine may be examined by microscopy of sediment or by filtration of a known volume through Nuclepore filters. Sensitivity can be further improved by testing for parasite DNA in urine sediment. The Kato thick smear and Nuclepore filtration provide quantitative data on the intensity of infection, which is of value in assessing the degree of tissue damage and in monitoring the effect of chemotherapy. Schistosome infection may also be diagnosed by examination of tissue specimens, typically rectal biopsy samples; except in rare circumstances, other biopsy procedures (e.g., liver biopsy) are not needed.
++
The differential diagnosis of schistosomal hepatomegaly must include viral hepatitis of all etiologies, miliary tuberculosis, malaria, visceral leishmaniasis, ethanol abuse, and causes of hepatic and portal vein obstruction. The differential diagnosis of hematuria in S. haematobium infection includes bacterial cystitis, tuberculosis, urinary stones, and malignancy.
++
TREATMENT Schistosomiasis
Treatment of schistosomiasis depends on the stage of infection and the clinical presentation. Other than topical dermatologic applications for relief of itching, no specific treatment is indicated for cercarial dermatitis caused by avian schistosomes. Therapy for acute schistosomiasis or Katayama syndrome needs to be adjusted appropriately for each case. Although antischistosomal chemotherapy may be used, it does not have a significant impact on maturing worms. In severe acute schistosomiasis, management in an acute-care setting is necessary, with supportive measures and consideration of glucocorticoid treatment to reduce inflammation. Once the acute critical phase is over, specific chemotherapy is indicated for parasite elimination. For all individuals with established infection, treatment to eradicate the parasite should be administered. The drug of choice is praziquantel, which—depending on the infecting species (Table 134-2)—is administered PO as a total of 40 or 60 mg/kg in two or three doses over a single day. Praziquantel treatment results in parasitologic cure in ~85% of cases and reduces egg counts by >90%. Efficacy rates among children <5 years old have been reported to be lower. These children are more likely to need re-treatment to effect a cure. Few side effects have been encountered, and those that do develop usually do not interfere with completion of treatment. Dependence on a single chemotherapeutic agent has raised the possibility of development of resistance in schistosomes; to date, such resistance does not seem to be clinically significant. The effect of antischistosomal treatment on disease manifestations varies by stage. Early hepatomegaly and bladder lesions are known to resolve after chemotherapy, but the late established manifestations, such as fibrosis, do not recede. Additional management modalities are needed for individuals with other manifestations, such as hepatocellular failure or recurrent hematemesis. The use of these interventions is guided by general medical and surgical principles.
++
+++
PREVENTION AND CONTROL
++
Transmission of schistosomiasis is dependent on human behavior. Because the geographic distribution of infections in endemic regions of the world is not clearly demarcated, it is prudent for travelers to endemic areas to avoid contact with all freshwater bodies, irrespective of the speed of water flow or unsubstantiated claims of safety. Some topical agents, when applied to the skin, may inhibit cercarial penetration, but none is currently available. If exposure occurs, a follow-up visit with a health care provider is strongly recommended. Prevention of infection in inhabitants of endemic areas is a significant challenge. Residents of these regions use freshwater bodies for sanitary, domestic, recreational, and agricultural purposes. Several control measures have been used, including application of molluscicides, provision of sanitary water and sewage disposal, chemotherapy, and health education to effect behavioral change in terms of water-contact activities. Current recommendations to countries endemic for schistosomiasis emphasize the use of multiple approaches. With the advent of an oral, safe, and effective broad-spectrum antischistosomal agent (praziquantel), chemotherapy has been most successful in reducing the intensity of infection and reversing disease. The duration of this positive impact depends on the transmission dynamics of the parasite in any specific endemic region. The ultimate goal of research on prevention and control is the development of a vaccine. Although there are a few promising leads, this goal probably is not within reach during the next decade.