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Schistosomes are well adapted to the human host and generally establish a balanced host-parasite relationship. As a result, the majority of infected people are asymptomatic or have only mild nonspecific symptoms. Severe symptoms and major clinical sequelae occur in approximately 10-15% of the infected populations without treatment. The life expectancy of patients with mild schistosomiasis is probably not substantially shorter than that of uninfected individuals living in the same geographic area. Prior to the development of effective treatment, approximately 1% of the infected population died each year, generally as a result of bleeding esophageal varices, renal failure or an associated malignancy (Hinz, 1985). The clinical importance of schisto-somiasis, however, has probably been greatly underestimated in the past. Morbid sequelae are common, and growing children, pregnant women and the most malnourished segments of a population probably suffer disproportionately from infection (Stephenson and Holland, 1987; Olds et al, 1996).

Acute Schistosomiasis

Most people become infected with schistosomes asymptomatically. In a small percentage of patients, an immediate itching and urticaria is seen at the site of cercarial penetration. Often referred to as 'schistosome dermatitis', it may progress into papular lesions that can persist for 5-7 days (Amer, 1994). This condition is far more common when non-human schistosome cercariae penetrate the skin (e.g. avian schistosomal cercariae) and is called swimmer's itch.

Migration of schistosomulae in the venous system, arterial bed and specific venous beds may be associated with mechanical and inflammatory changes in the lung and liver but generally is also asymptomatic. As worms mature in the liver, migrate to the small venules and begin to lay eggs, a second form of acute schistosomiasis may be observed, termed Katayama fever (Warren, 1973a). Symptoms generally have an acute onset, 3-6 weeks after a heavy exposure to cercariae. Spiking fever with chills, myalgia, headache, diarrhea, fatigue and weight loss are observed. Nausea, vomiting and cough are common. Occasionally, hepatosplenic enlargement is seen. Large patches of urticaria may also be seen on various parts of the body.

Katayama fever is thought to represent a form of serum sickness in which a rising antibody titer

Fig. 16.5 Two boys with schistosomiasis and hepato-splenomegaly occurs in the setting of significant antigen production from freshly deposited ova (Hiatt et al., 1980). Patients can be quite ill and occasional fatalities have been reported. Katayama fever appears to be more common in Asia, but has been reported for all species. It may also be more common in heavy infections of a naive host or on massive reinfection after a significant time interval. Fever subsides 2-10 weeks after the onset even without treatment (Lawley et al., 1979). Aggressive treatment with antiparasitic agents and immunosuppression probably alter the course of illness.

Intestinal Schistosomiasis (S. mansoni, S. japonicum, S. mekongi)

Non-specific symptoms, such as abdominal pain and malaise, are common. Intermittent diarrhea is the most common symptom of intestinal involvement and may alternate with constipation. The stool may occasionally contain blood and mucus. Frank schistosomal dysentery is uncommon (Cheever, 1978). A severe form of intestinal involvement is colonic polyposis (El Masry et al., 1986). This condition generally effects young males and, in addition to bloody diarrhea, protein-losing enteropathy, hypo-kalemia and severe dehydration are often found. On sigmoidoscopy and biopsy, intense granulomatous inflammation with parasite ova is found. Occasionally, inflammatory masses are observed along the colon and need to be differentiated from malignant lesions (Mohamed et al., 1990). Intestinal schistosomiasis is most commonly confused clinically with ulcerative colitis or Crohn's disease and occasional abdominal tuberculosis. The condition responds well to effective antiparasitic treatment.

Hepatosplenic Disease (S. haematobium, S. japonicum, S. mekongi)

The clinical manifestations of chronic hepatosplenic schistosomiasis are shown in Table 16.3, the most common being enlargement of the liver (Nooman et al., 1974). Hepatic enlargement is diffuse and non-tender. A firm liver edge is palpable below the mid-clavicular and mid-sternal lines. Hepatic enlargement commonly develops 6 months to 2 years after initial infection (or re-infection) and is primarily a result of granulomatous inflammation (Warren, 1984; Dunn and Kamel, 1981). During this stage, 50-90% of individuals may have palpable hepatomegaly, particularly children. Two such children are shown in Figure 16.5. The classic fibrotic lesions have been reported on liver biopsy as early as 80 days after exposure, but the clinical manifestations generally take months to years to develop. Multiple exposures are probably required to acquire a sufficient number of eggs and the associated granulomas to produce symptomatic disease. Prothrombin time is only mildly prolonged and transaminases are normal or mildly elevated in pure schistosome-induced liver disease (Dunn and Kamel, 1981). Serum alkaline phosphatase and bilirubin are also

Fig. 16.5 Two boys with schistosomiasis and hepato-splenomegaly normal or mildly elevated. Jaundice, ascites and encephalopathy are manifestations of hepato-cellular decompensation and are unusual in pure schistosomiasis (Elliott, 1996b). Because patients with portal hypertension secondary to schistoso-miasis tolerate episodes of variceal bleeding much better than those with cirrhosis, repeated non-fatal episodes of bleeding are common (Raia et al., 1984).

Enlargement of the spleen is quite common when sensitive tests such as ultrasound are used. Palpable splenomegaly occurs less commonly. Massive splenomegaly, often as much as 8-12 cm below the left costal margin, is found in less than 5% of untreated cases. Hypersplenism with thrombocytopenia occurs rarely. Hypoalbumine-mia and hypergammaglobulinemia are seen in less than 25% of patients. Anemia is very common and is multifactorial, including acute or chronic blood loss, hypersplenism and anemia of chronic disease, as well as the fact that adult worms ingest red blood cells. Hepatosplenic enlargement generally responds well to curative chemotherapy (Ohmae et al., 1992).

Ascites is seen in late hepatosplenic disease and results from both portal hypertension and hypoalbuminemia. Low albumin can result from intestinal loss, associated nephrotic syndrome, and from co-morbid conditions such as hepatitis B or C. The 'swollen bellies' of schistosomiasis have been used to identify schistosomiasis-endemic communities historically. The condition is most commonly seen in males 16-25 years of age. At this stage, endorgan damage may not be reversible with drugs.

Prior to the development of effective chemotherapy, most patients did not develop severe hepatosplenic schistosomiasis despite years of chronic infection. The degree of fibrosis also does not correlate well with either the size of the liver or the presence of splenic enlargement. In humans, the pathologic progression is therefore highly variable and could develop within a few months in heavily infected patients but more commonly develops over many years and in only a small subset. Most evidence suggests the hepatosplenic schistosomiasis in humans is a result of the inflammatory injury accumulated over years of moderately intense schistosomal infection (Dunn and Kamel, 1981). Some individuals may be particularly genetically susceptible to the pathologic sequelae of schistosomiasis (Abdul-Salem et al, 1986). In addition, individuals who fail to 'modulate' their infection immunologically may progress more rapidly and suffer greater pathology (Olds et al., 1996).

Genitourinary Involvement (S. haematobium)

Urinary frequency and dysuria are early symptoms of S. haematobium infection, but hematuria is the classic presenting feature (Smith and Christie, 1986). S. haematobium is so common in endemic areas of upper Egypt that it is culturally considered the equivalent of the male menarche. Intermittent terminal hematuria, dys-uria and urinary frequency are characteristic of vesical involvement. Suprapubic or perineal pain may occur intermittently, with bladder distention (Smith et al., 1977). Hydronephrosis from granulomas in the bladder wall, ureters and urethra is the most common clinical sequela. Hydronephrosis, pyelonephritis and recurrent urinary tract infection may be due to progressive ureteral obstruction (Lehman et al., 1973). Late sequelae include clinical presentation of acute or chronic renal failure or squamous cell carcinoma of the bladder (Thomas et al., 1990). This diagnosis should be entertained in an individual presenting with hematuria from an endemic country or in those suspected of having a malignancy of the bladder or kidney. Urinary tract ultrasound, urine cytologies and even biopsy material have been misdiagnosed as malignant by physicians unfamiliar with this disease. Most early pathology responds well to treatment.

Vaginal schistosomiasis was reported in Egypt around the turn of the 19th-20th century. Recently, genital disease has been described, not necessarily involving the bladder and ureters (Wright et al., 1982). The maximal age of involvement is older than classically described for S. haematobium and may be found in women with very few eggs in their urine. In one community-based study from Africa, 30-75% of women infected with S. haematobium had egg-associated lesions in their lower reproductive tract (Poggensa et al., 1998). In Madagascar,

43% of boys and men aged 15-49 had S. haematobium eggs in their semen and genital schistosomiasis (Leutscher et al., 1998). These findings have now increased in importance, since they may increase the risk of acquiring HIV infection and could predispose to cervical cancer (Helling-Giese et al., 1996). Patients generally respond well to chemotherapy.

Nephrotic syndrome is occasionally seen in association with hepatosplenic schistosomiasis (Farid et al., 1972; Andrade and Rocha, 1979). It responds well to treatment if this is initiated early in the course of disease.

Association with Other Infections Salmonella

Persistent Salmonella bacteremia has been well described with S. mansoni and occasionally seen in S. japonicum (Rocha et al., 1971). The organism is not always S. typhi and often has a delayed clinical presentation. Patients often do not appear acutely ill, but generally have a low-grade fever. Most patients with dual infections (schistosomiasis and salmonellosis) have hepato-splenic enlargement. Patients respond promptly to antibodies but frequently relapse (Neves et al., 1969). Salmonella has been isolated from the tegument and intestinal tract of adult S. mansoni worms and the adult worms are thought to serve as a protected intravascular reservoir for bacter-ologic relapse (Ottens and Dickerson, 1972). Treatment of schistosomiasis alone cures 90% of patients. Dual treatment is recommended. Salmonella urinary tract infections are also described with S. haematobium, but bacteremia is less common (Farid et al., 1970). Dual treatment is recommended, but occasionally infected calculi complicate management.

Hepatitis

Co-infections with hepatitis B and C have been reported to be more common in patients with schistosomiasis than in the general population (El-Rooby, 1985; Koshy etal, 1993; Gang, 1993). This could be due to the administration of injectable drugs or blood transfusions used to treat schistosomiasis prior to the 1980s (Madwar et al., 1989). In addition, it has been suggested that immunologic responses to chronic schistosomiasis may interfere with the development of a curative immune response to hepatitis, contributing to more severe hepatic sequelae of co-infection.

Cancer

Chronic schistosomiasis may increase the risk of several types of cancer. S. haematobium infection results in squamous metaplasia of the urinary bladder and urethral mucosa (Cheever, 1978; Chen and Mott, 1989). A clear association of S. haematobium infection with squamous cell cancer of the lower urinary tract has been established (Elsebai, 1977; Thomas et al., 1990; Obafunwa, 1991). The risk of malignant transformation may persist even after parasitologic cure.

S. mansoni infections may be associated with the development of inflammatory pseudopolyps of the colon (Mohamed et al., 1990; Strickland, 1994). These polyps, however, do not contain dysplastic epithelium and therefore are not thought to have a malignant potential. Anecdotal reports of an association between S. mansoni infection and lymphoma, hepatocellular carcinoma, or colorectal cancer have not, however, been supported by epidemiologic or prospective cohort studies (Johnstone, 1990; Chen and Mott, 1988; Cheever, 1981). Giant follicular lymphoma may develop in the spleen of patients with chronic severe hepatosplenic schistosomiasis (Andrade, 1971a). An association between hepatocellular and colonic cancer has been suggested with S. japonicum but epidemiologic studies from China and Japan do not support this association (Gang, 1993; Nakashima et al., 1975; Li et al., 1991, 1993).

DIAGNOSIS Current Approach

Since most people infected with schistosomiasis are asymptomatic, a high index of suspicion is required to clinically identify infection, especially in geographic areas where infection is uncommon. The diagnosis should be considered in any patient with a possible exposure history who presents with fever, eosinophilia, hepatospleno-megaly, anemia, hematuria, obstructive uropathy, recurrent urinary tract infection (especially with Salmonella), glomerulonephritis, seizures, transverse myelitis, pulmonary hypertension or cor pulmonale.

In addition, asymptomatic infection, e.g. travelers, should be actively screened for. Suspicion should be particularly high in an individual with esophageal varices, hepatic enlargement and normal liver function tests (El Rooby, 1985; Raia et al., 1984). Most other etiologies for bleeding varices result in small cirrhotic livers, elevation in transaminases and low serum albumin. Travel history, history of contact with fresh water, skin rash or acute febrile episodes should be specifically elicited. A definitive diagnosis is made by identification of the characteristic schistosome eggs in feces, urine or a biopsy specimen (Feldmeier, 1993). The excretion of eggs may be scanty or absent in the early phase of illness and repetitive examinations are recommended, using the appropriate stool or urine concentration techniques (World Health Organization, 1983; Peters and Kazura, 1987). Parasite eggs may also be absent or in low numbers in patients who present with chronic fibrotic complications of schistosomiasis.

Hematuria is often used as a marker for infection in endemic areas and empiric treatment initiated without parasitologic confirmation (Taylor et al., 1990). In order to increase the diagnostic utility of the reagent strip test of hematuria, additional measurement of protein-uria and leukocyturia have been suggested (Kaiser et al., 1992).

Stool Diagnosis

S. mansoni, S. japonicum, S. intercalatum and S. mekongi are diagnosed using stool samples. Various concentration methods can be used, including a formol-ether, merthiolate-iodine-formol method, Bell filtration method using ninhydrin as the stain, or the Kato method using glycolmalachite green (Bailenger, 1979; Bell, 1963; Feldmeier, 1993; Martin and Bearer, 1968; Katz et al., 1970). The most common method for the detection of eggs in stool is the Kato-Katz thick smear technique. This technique is inexpensive, quick to perform and has been adapted for use in the field. It also allows quantification of the intensity of infection. Standard wet mounts do not contain a large enough sample to reliably find schistosome eggs, and the standard zinc sulfate sedimentation method does not recover schistosome eggs (Elliott, 1996b). Flotation methods of concentration should not be used if schistosomiasis is suspected, because schistosome eggs do not float on the usual solvents because of their weight. It is therefore imperative that the laboratory be notified about the possible diagnosis of schisto-somiasis.

The Kato-Katz thick smear preparation is based on the principle of using glycerol to clarify the stool sample. That enables the eggs to be easily visualized microscopically (Katz et al., 1970). This increases the accuracy of diagnosis under field conditions and is now used in all national control programs (Katz et al., 1970; Teesdale and Amin, 1976). It is an inexpensive, non-invasive, highly specific test with an acceptable sensitivity. Low-level infection may not be diagnosed by the standard triplicate Kato-Katz thick smear using a single stool specimen. Sensitivity is improved if multiple stool samples are examined (Sleigh et al., 1982; Katz et al., 1970). This is particularly true in S. japonicum, where significant stool/stool variations in egg counts have been documented. One limitation of the standard Kato-Katz technique is the requirement for at least 8-12 hours to clear the slide. This time requirement is suboptimal for walk-in clinics, where it is preferable to treat people before they leave. A quick Kato technique has been developed for this purpose that can be read in 2 hours (Engels et al., 1996).

Urine Diagnosis

The eggs of S. haematobium are passed in the urine with diurnal periodicity, with peak excretion between mid-morning and mid-afternoon (Doehring et al., 1985). Urine collected during this period may be concentrated by simple sedimentation or passing the urine through a cellulose filter to concentrate the parasite eggs. The latter allows quantification of infection. Filtration techniques that give quantitative assessment of egg excretion are replacing the simple sedimentation or centrifugation techniques (Dazo and Biles, 1974).

Viability

Viable ova can be hatched from specimens and the diagnosis made by examining for miracidia (Braun-Munzinger and Southgate, 1993). Mixing the ova (in stool or urine) in water and exposing them to light results in miracidia in the supernatant in a few hours. All species of schistosomiasis can be diagnosed using a variety of these egg-hatching techniques (Weber, 1973). These techniques are quite labor-intensive and non-quantifiable, but they can be more sensitive than a single stool examination (Braun-Munzinger and Southgate, 1993).

Biopsy

Eggs can be found in biopsy specimens in all schistosome species. Rectal biopsy has been considered to be the most sensitive method to diagnose schistosomiasis when repeated stools are negative (Abdel-Hafez and Bolbol, 1992). Biopsy specimens may show mucosal inflammation with eosinophilic infiltration. A granulomatous response surrounding a viable egg is diagnostic of schistosomiasis. Crushing the biopsy specimen between slides and surveying the entire sample microscopically increases the diagnostic sensitivity (Feldmeier, 1993). Six biopsy specimens examined after crushing are more sensitive than duplicate Kato-Katz stool smears (Abdel-Wahab et al., 1992). A single rectal biopsy specimen, however, is less sensitive than multiple Kato-Katz smears.

Ultrasound

One of the most important advances in the diagnosis of chronic schistosomiasis is the use of ultrasound (Hatz et al., 1992). This technique can not only diagnose schistosome-induced liver disease but determines the grade of hepatic fibrosis (Abdel-Wahab et al., 1992). Comparison of ultrasound with open liver biopsies has confirmed the accuracy of this approach (Cerri et al., 1984; Homeida et al., 1988). The World Health Organization (1991) has developed a standardized scale for comparative evaluation. Several double-blind studies have demonstrated that the ultrasonographic appearance of multiple echogenic areas with central lucency in the liver is highly suggestive of hepatic schistosomiasis (Hussain et al., 1984). This is particularly true for World Health Organization Grades II and III fibrosis. Unfortunately, many other diseases can be confused with Grade I or minimal periportal fibrosis, including acute hepatitis, tuberculosis and salmonellosis. Grade I fibrosis can even occasionally be confused with a normal liver. As a result, ultrasound is only diagnostic when schistosomal damage is extensive. Many patients with early schistosomiasis have normal or nonspecific changes on ultrasound (Hussain et al., 1984; Olds et al., 1996; Abdel-Wahab et al., 1992). It is particularly common for children to have an enlarged liver on echo without evidence of periportal fibrosis. Ultrasonography is also superior to physical examination in the documentation of hepatomegaly and splenomegaly, particularly for large population-based studies (Hussain et al., 1984; Olveda et al., 1996; Wiest et al., 1992). Ultrasonography has also been shown to be useful in follow-up of the hepatic fibrosis and hepatosplenic enlargement, especially in patients treated with schistosomicidal drugs (Doehring-Schwerdtfeger et al., 1992; Ali et al., 1991; Wiest et al., 1992). Ultrasound is also useful in the diagnosis of urinary schistosomiasis but other pathologies can appear similar, including urinary tuberculosis and several malignant lesions (Jenkins and Hatz, 1992). Cystoscopy with biopsy is recommended if ova cannot be recovered and urine cytologies are negative (Feldmeier et al., 1981).

Liver Biopsy

The diagnosis of schistosomal-induced liver disease has classically required an open wedge biopsy. Sampling error and the limited tissue obtained make percutaneous liver biopsy an insensitive method for the detection of schistosome eggs (Maharaj et al., 1986). With the advent of non-invasive tools such as abdominal ultrasound, liver biopsy is no longer used to specifically diagnose schistosomiasis. Liver biopsy is helpful to establish or rule out other co-morbid conditions, such as hepatitis B or C-related disease or alcoholic cirrhosis.

Serodiagnosis

The labor-intensive nature of stool and urine examinations and the logistical difficulty of obtaining specimens have directed attention to serodiagnostic tests. Antibodies against schisto-somes remain elevated even after the resolution of infection (Maddison, 1987). Detection of antischistosome antibodies in endemic areas, therefore, has limited utility (Bergquist, 1992). Serodiagnosis based on antibodies does, however, have a role in confirming exposure to mature schistosomes in travelers visiting endemic areas (Feldmeier, 1993).

Serodiagnosis is helpful in the diagnosis of acute schistosomiasis (since the clinical manifestations can occur prior to eggs appearing in the stool or urine). An antibody assay system that utilizes the cross-reactivity between keyhole limpet (Megathura crenulata; KHL) and schisto-some carbohydrate antigens has been used to diagnose acute schistosomiasis (Grzych et al., 1987). In acute schistosomiasis, antibodies to KHL develop rapidly and then wane during chronic infection (Alves-Brito et al., 1992). Thus, KHL reactivity carries the same implications as IgM antibody titers in most other infectious diseases.

Detection of circulating schistosomal antigens in blood or urine can identify patients with active infection. Circulating antigen disappears after parasitologic cure, making this an attractive option for use in endemic countries. Based on the electrophoretic affinity, two antigens have been identified and extensively tested for this purpose: circulating anodic (CAA) and cathodic (CCA) adult worm antigens (Deelder et al., 1994). These are proteoglycan gut-associated antigens that are a part of the heterogeneous group of antigens derived from the gut of the parasites. These are released by the regurgitation of digested blood and indicate an active infection with viable worms (Nash and Deelder, 1985). The serum levels of these circulating antigens can be detected by the use of monoclonal antibodies, which are very specific (Gundersen et al., 1992). These antigens (and their enzymatic breakdown products) appear in the urine, and thus a urine-based antigen detection system is feasible and would be a very attractive diagnostic test for field applications. A prototype is currently under development in Europe. Serum and urine antigen titers correlate with the intensity of infection, as determined by egg counts (DeJonge et al., 1988; Van Wout et al., 1992). The antigen assay systems are not yet commercially available and are not currently more sensitive than multiple stool or urine exams for ova. The concentrations of CAA or CCA do not vary significantly over short periods of time (van Leishout et al., 1991). It has been shown that parasitologic cure or drug failure can be detected as early as 10 days after treatment (Barsoum et al., 1991; Van Wout et al., 1992). The antigen assays also avoid the day-today, or circadian, variations observed with egg excretion and aid in the assessment of response to chemotherapy. The major limitations of antigen assays include: the cost of highly purified monoclonal antibodies needed; expensive biochemical reagents with a short half-life; and the need for trained technicians. These make antigen assay systems of limited utility, even in developed countries. As a result, multiple stool examinations remain the most sensitive and cost-effective way to diagnose schistosomiasis today. When negative, given the low toxicity of praziquantel, empiric treatment is generally considered preferable to multiple rectal biopsies in suspected cases (Deelder et al., 1994).

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