CHAPTER 134: SCHISTOSOMIASIS AND OTHER TREMATODE INFECTIONS

Trematodes, or flatworms, are a group of morphologically and biologically heterogeneous organisms that belong to the phylum Platyhelminthes. Human infection with trematodes occurs in many geographic areas and can cause considerable morbidity and mortality. The dependence on one drug—praziquantel—for treatment of most infections caused by trematodes raises the specter of developing resistance in these worms; several instances of reduced drug efficacy have already been reported. The widespread use of oxamniquine in the 1970s to reduce the impact of schistosomiasis resulted in the development of significant resistance. Recently, a single quantitative trait locus on schistosomal chromosome 6 was identified as the genetic basis for resistance.

For clinical purposes, significant trematode infections of humans may be divided according to the tissues invaded by the adult stage of the fluke, whether bloodstream, biliary tree, intestines, or lungs (Table 134-1). Trematodes share some common morphologic features, including macroscopic size (from one to several centimeters); dorsoventral, flattened, bilaterally symmetric bodies (adult worms); and the prominence of two suckers. Except for schistosomes, all human parasitic trematodes are hermaphroditic. Their life cycles involve a definitive host (mammalian/human), in which adult worms initiate sexual reproduction, and an intermediate host (snail), in which asexual multiplication of larvae occurs. More than one intermediate host may be necessary for some species of trematodes. Human infection is initiated either by direct penetration of intact skin or by ingestion. Upon maturation within humans, adult flukes initiate sexual reproduction and egg production. Helminth ova leave the definitive host in excreta or sputum and, upon reaching suitable environmental conditions, they hatch, releasing free-living miracidia that seek specific snail intermediate hosts. After asexual reproduction, cercariae are released from infected snails. In certain species, these organisms infect humans; in others, they find a second intermediate host to allow encystment into metacercariae—the infective stage for humans.

The host-parasite relationship in trematode infections is a product of certain biologic features of these organisms: they are multicellular, undergo several developmental changes within the host, and usually result in chronic infections. In general, the distribution of worm infections in human populations is overdispersed; i.e., it follows a negative binomial statistical distribution in which most infected individuals harbor low worm burdens while a small percentage are heavily infected. It is the heavily infected minority who are particularly prone to disease sequelae and who constitute an epidemiologically significant reservoir of infection in endemic areas. Recent evidence indicates that the prevalence of morbidity in infected populations is greater than was previously thought. Morbidity and death due to trematode infections reflect a multifactorial process that results from the tipping of a delicate balance between intensity of infection and host reactions, which initiate and modulate immunologic and pathologic outcome. Furthermore, the genetics of the parasite and of the human host contribute to the outcome of infection and disease. Infections with trematodes that migrate through or reside in host tissues are associated with a moderate to high degree of peripheral-blood eosinophilia; this association is of significance in protective and immunopathologic sequelae and is a useful clinical indicator of infection.

Except among international travelers, trematode infections are quite rare in high-income countries because good sanitation and hygiene block trematode transmission and because transmission is tied to the distribution of the specific snail species that serve as intermediate hosts during the parasites’ life cycle. In contrast, parasitic fluke infections are quite common in underdeveloped areas of Africa, Asia, and South America, with an estimated 440 million people affected by past or present Schistosoma infection and another 60 million people affected by the other foodborne trematodes. These infections are not benign; they result in multiyear chronic inflammatory disorders that significantly affect performance status and health-related quality of life. Global disease burden estimates indicate that at least 5 million years of healthy life are lost each year in the more than 90 endemic countries around the world.

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.

ETIOLOGY

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.

EPIDEMIOLOGY

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.

CLINICAL FEATURES

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.

DIAGNOSIS

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

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.

Several species of biliary fluke infecting humans are particularly common in Southeast Asia and Russia. Other species are transmitted in Europe, Africa, and the Americas. On the basis of their migratory pathway in humans, these infections may be divided into the Clonorchis and Fasciola groups (Table 134-1).

CLONORCHIASIS AND OPISTHORCHIASIS

Infection with Clonorchis sinensis, the Chinese or oriental fluke, is endemic among fish-eating mammals in Southeast Asia. Humans are an incidental host; the prevalence of human infection is highest in China, Vietnam, and Korea. Infection with Opisthorchis viverrini and O. felineus is zoonotic in cats and dogs. Transmission to humans occurs occasionally, particularly in Thailand (O. viverrini) and in Southeast Asia and eastern Europe (O. felineus). Data on the exact geographic distribution of these infectious agents in human populations are rudimentary.

Infection with any of these three species is established by ingestion of raw or inadequately cooked freshwater fish harboring metacercariae. These organisms excyst in the duodenum, releasing larvae that travel through the ampulla of Vater and mature into adult worms in bile canaliculi. Mature flukes are flat and elongated, measuring 1–2 cm in length. The hermaphroditic worms reproduce by releasing small operculated eggs, which pass with bile into the intestines and are voided with stools. The life cycle is completed in the environment in specific freshwater snails (the first intermediate host) along with later encystment of snail-derived cercariae as infectious metacercariae in freshwater fish.

Except for late sequelae, the exact clinical syndromes caused by clonorchiasis and opisthorchiasis are not well defined. Because most infected individuals harbor a low worm burden, many are minimally symptomatic. Moderate to heavy infection may be associated with vague right-upper-quadrant pain. In contrast, chronic or repeated infection is associated with manifestations such as cholangitis, cholangiohepatitis, and biliary obstruction. Cholangiocarcinoma is epidemiologically related to C. sinensis infection in China and to O. viverrini infection in northeastern Thailand. This association has resulted in classification of these infectious agents as human carcinogens.

FASCIOLIASIS

Infections with Fasciola hepatica and F. gigantica are worldwide zoonoses that are particularly endemic in sheep-raising countries. Human cases have been reported in South America, Europe, Africa, and Australia. Recent estimates indicate a worldwide prevalence of 17 million cases. High endemicity has been reported in certain areas of Peru and Bolivia. In most endemic areas the predominant species is F. hepatica, but in Asia and Africa a varying degree of overlap with F. gigantica has been observed.

Humans acquire fascioliasis by ingestion of metacercariae attached to certain aquatic plants, such as watercress, water caltrop, and water chestnuts. Infection may also be acquired by consumption of contaminated water or ingestion of food items washed with such water. Acquisition of human infection through consumption of freshly prepared raw liver containing immature flukes has been reported. Infection is initiated when metacercariae excyst, penetrate the gut wall, and travel through the peritoneal cavity to invade the liver capsule. Adult worms migrate through the liver parenchyma and finally reach bile ducts, where they produce large operculated eggs that are voided in bile through the gastrointestinal tract to the outside environment. The flukes’ life cycle is completed in specific snails (the first intermediate host) followed by encystment on aquatic plants.

Clinical features of fascioliasis relate to the stage and intensity of infection. Acute disease develops during parasite migration (1–2 weeks after infection) and includes fever, right-upper-quadrant pain, hepatomegaly, and eosinophilia. Computed tomography (CT) of the liver may show multiple parenchymal holes/or migratory tracks. Symptoms and signs usually subside as the parasites reach their final habitat. In individuals with chronic infection, bile duct obstruction and biliary cirrhosis are infrequently demonstrated. No relation to hepatic malignancy has been ascribed to fascioliasis.

DIAGNOSIS

Diagnosis of infection with any of the biliary flukes depends on a high degree of suspicion, elicitation of an appropriate geographic history, and stool examination for characteristically shaped parasite ova. Additional evidence may be obtained by documenting peripheral-blood eosinophilia or imaging the liver. Serologic testing is helpful, particularly in lightly infected individuals.

TREATMENT

Two species of intestinal flukes cause human infection in defined geographic areas worldwide (Table 134-1). The large Fasciolopsis buski (adults measure 2 × 7 cm) is endemic in Southeast Asia, whereas the smaller Heterophyes heterophyes is found in the Nile Delta of Egypt. Infection is initiated by ingestion of metacercariae attached to aquatic plants (F. buski) or encysted in freshwater or brackish-water fish (H. heterophyes). Flukes mature in human intestines, and eggs are passed with stools. Most individuals infected with intestinal flukes are asymptomatic. In heavy F. buski infection, diarrhea, abdominal pain, and malabsorption may be encountered. Heavy infection with H. heterophyes may be associated with abdominal pain and mucous diarrhea. The diagnosis is established by detection of characteristically shaped ova in stool samples. The drug of choice for treatment is praziquantel (Table 134-2).

Infection with the lung fluke Paragonimus westermani (Table 134-1) and related species (e.g., P. africanus) is endemic in many parts of the world, excluding North America and Europe. Endemicity is particularly noticeable in West Africa, Central and South America, and Asia. In nature, the reservoir hosts of P. westermani are wild and domestic felines. In Africa, P. africanus has been found in other species, such as dogs. Adult lung flukes, which are 7–12 mm in length, are found encapsulated in the lungs of infected persons. In rare circumstances, flukes are found encysted in the CNS (cerebral paragonimiasis) or the abdominal cavity. Humans acquire lung fluke infection by ingesting infective metacercariae encysted in the muscles and viscera of crayfish and freshwater crabs. In endemic areas, these crustaceans are consumed raw, marinated, or pickled. Once the organisms reach the duodenum, they excyst, penetrate the gut wall, and travel through the peritoneal cavity, diaphragm, and pleural space to reach the lungs. Mature flukes are found in the bronchioles surrounded by cystic lesions. Parasite eggs are either expectorated with sputum or swallowed and passed to the outside environment with feces. The life cycle is completed in snails and freshwater crustaceans.

When maturing flukes lodge in lung tissues, they cause hemorrhage and necrosis, resulting in cyst formation. The adjacent lung parenchyma shows evidence of inflammatory infiltration, predominantly by eosinophils. Cysts usually measure 1–2 cm in diameter and may contain one or two worms each. With the onset of oviposition, cysts usually rupture in adjacent bronchioles—an event allowing ova to exit the human host. Older cysts develop thickened walls, which may undergo calcification. During the active phase of paragonimiasis, lung tissues surrounding parasite cysts may show evidence of pneumonia, bronchitis, bronchiectasis, and fibrosis.

Pulmonary paragonimiasis is particularly symptomatic in persons with moderate to heavy infection. Productive cough with brownish sputum or frank hemoptysis associated with peripheral-blood eosinophilia is usually the presenting feature. Chest examination may reveal signs of pleurisy. In chronic cases, bronchitis or bronchiectasis may predominate, but these conditions rarely proceed to lung abscess. Imaging of the lungs demonstrates characteristic features, including patchy densities, cavities, pleural effusion, and ring shadows. Cerebral paragonimiasis presents as either space-occupying lesions or epilepsy.

DIAGNOSIS

Pulmonary paragonimiasis is diagnosed by detection of parasite ova in sputum and/or stools. Serology is of considerable help in egg-negative cases and in cerebral paragonimiasis. The differential diagnosis includes active tuberculosis, bacterial lung abscess, and lung carcinoma.

TREATMENT

For residents of nonendemic areas who are visiting an endemic region, the only effective preventive measure is to avoid ingestion of local plants, fish, or crustaceans; if their ingestion is necessary, these items should be washed and cooked thoroughly. Instruction on water and food preparation and consumption should be included in physicians’ advice to travelers (Chap. 6). Interruption of transmission among residents of endemic areas depends on avoiding ingestion of infective stages and disposing of feces and sputum appropriately to prevent hatching of eggs in the environment. These two approaches rely greatly on socioeconomic development, health education, and significant behavioral change. In countries where economic progress has resulted in financial and social improvements, transmission has decreased. The third approach to control in endemic communities entails selective use of chemotherapy for individuals posing the highest risk of transmission (i.e., those with heavy infections). The availability of praziquantel—a broad-spectrum, safe, and effective anthelmintic agent—provides a means for reducing the reservoirs of infection in human populations. However, the existence of most of these helminthic infections as zoonoses in several animal species complicates control efforts.