Jennifer Keiser and Jürg Utzinger
Hundreds of millions of people, particularly those who live in rural areas or deprived urban settings in the developing world, are at risk of acquiring foodborne trematodiasis and schistosomiasis.1-3
Foodborne trematodiasis include clonorchiasis, paragonimiasis, fascioliasis, and opisthorchiasis. These and schistosomiasis all belong to the subclass of Digenea, class of Trematoda, phylum of Platyhelminthes. The taxonomy of Platyhelminthes is shown in eFigure 335.1 . Digeneans, also known as flatworms, are characterized by dorsoventral flattening, presence of an oral sucker and often a ventral sucker, and lack of a circulatory system.4Figure 335-1shows, by means of scanning electron microscopy, the head portion of an adult Clonorchis sinensis (a liver fluke), clearly depicting some of the typical features of the Digeneans.
EPIDEMIOLOGY
The endemic regions of the world, global burden and at risk populations for infection with clonorchiasis, fascioliasis, fasciolopsiasis, opisthorchiasis, paragonimiasis, and schistosomiasis are summarized in Table 335-1.3,5-10
The major species from the subclass Digenea parasitizing humans include the blood flukes (5 species of Schistosoma), liver flukes (C sinensis, Fasciola gigantica, F hepatica, Opisthorchis felineus, and O viverrini), lung flukes (Paragonimus spp), and intestinal flukes (eg, Fasciolopsis buski).
FIGURE 335-1. Scanning electron microscopic image of the head portion of an adult Clonorchis sinensis fluke (OS, oral sucker; VS, ventral sucker).
Schistosomiasis exhibits the largest geographic distribution; the disease is endemic in over 70 countries and territories of the world with an estimated 779 million people at risk and 207 million infections (eFig. 335.2 ).3 The global burden due to schistosomiasis might be as high as 4.5 million disability-adjusted life years (DALYs). The DALY is a metric used to express the number of healthy life years lost due to a disease or injury, taking into account both premature death and living with disabilities. DALYs are extremely difficult to calculate for helminthic diseases and other chronic conditions. Schistosoma haematobium and S mansoni are responsible for the majority of the disease burden, morbidity and mortality from schistosomiasis, with disease being concentrated in sub-Saharan Africa.3,11
An estimated 750 million people are at risk of foodborne trematodiasis with over 40 million infections. Southeast Asia and the Western Pacific are the regions most impacted by foodborne trematodiasis.2,12Estimates for at-risk populations for clonorchiasis, paragonimiasis, fascioliasis, and opisthorchiasis are 601 million, 293 million, 91 million, and greater than 60 million, respectively.
The patterns of age distribution of infections are not uniform, but in general the highest rates of infection with Schistosoma species, Fasciola species, and F buski is found among school-age children and young adults.9 On the other hand, in the case of clonorchiasis and opisthorchiasis, the prevalence of infection increases with age, and hence adults are more affected than their younger counterparts.8
Profound demographic, ecologic, and socioeconomic transformations have altered the epidemiology of schistosomiasis and foodborne trematodiasis. The development and management of water resources (ie, irrigation schemes and large dams) has resulted in outbreaks of schitosomiasis, or intensified disease transmission. Indeed, living in close proximity to such water resources is a key risk factor for acquiring the disease.3 Similarly, socio-economic changes including the expansion of aquaculture for production of freshwater fish and shrimp, inadequate sanitation, domestic migration, and wider distribution networks of food without proper inspections are some of the key features explaining an increase in foodborne trematodiasis.6
Table 335-1. Schistosomiasis and Foodborne Trematodiasis
The expansion of schistosomiasis and foodborne trematodiasis into previously nonendemic areas may also be partly explained by global warming and human modification of the landscape.9,13 In the case of foodborne trematodiasis, increases in international travel and growing consumption of imported aquatic foods may also play a role. On the other hand, socioeconomic development and implementation of morbidity control programs dramatically lowered the burden due to schistosomiasis and foodborne trematodiasis in some regions.3,6
PATHOPHYSIOLOGY
eFigure 335.3 shows the life cycle of the digeneans, distinguishing between schistosomes and foodborne trematodes. A characteristic feature is the alternation of asexual and sexual reproductive phases.4Parasite eggs are excreted from humans (or a range of domestic animals that can also act as definitive hosts in the sputum (Paragonimus spp), feces (C sinensis, Fasciola spp, Opisthorchis spp, Paragonimusspp, S mansoni, S japonicum, S intercalatum, and S mekongi), or urine (S haematobium). Once eggs have reached a freshwater body, they develop and release a tiny larva, the so-called miracidium, which seeks a specific snail species (usually small aquatic snails), the first intermediate host. Within the snail, larval development and asexual multiplication takes place and cercariae are released from snails.
Schistosoma cercariae infect humans subcutaneously when they come into contact with infested freshwater during recreational (eg, playing in stagnant freshwater ponds) and occupational activities (eg, irrigated rice farming). The tailless cercariae are transported through blood or lymphatics to the right side of the heart and lungs. The adult worms do not multiply inside the human body, but mate and the female lays eggs about 4 to 6 weeks following cercarial penetration. This phase of infection can be associated with Katayama fever (see below) which is believed to result from immune complex formation with high antigenic stimulation due to the worm or egg antigens. The female adult worm continues to live for up to 8 years and lays eggs throughout her life span. The chronic sequelae of Schistosomiasis are due to immunologic reactions to the eggs trapped in tissues that lead to a granulomatous reaction.
In the case of lung, liver, and intestinal flukes, the cercariae encyst in the flesh of the second intermediate hosts—fish (eg, C sinensis, Opisthorchis spp) or shellfish (eg, Paragonimus spp)—or encyst on aquatic plants (eg, Fasciolaspp, F buski). Humans become infected when eating raw or undercooked aquatic products harboring metacercariae.12 Upon ingestion, the acid environment of the stomach begins the process of excystment, and in the duodenum the worm burrows through the intestinal lining into the peritoneal cavity where it traverses to the lung, or through the liver to the bile ducts, where the mature worm resides and excretes eggs. The C sinensis, Fasciola spp and Opisthorchis spp reside in the bile ducts of the liver and eggs are excreted in stool. F buski resides in the duodenum. Paragonimus reside in the lungs and eggs are excreted in the sputum, or swallowed and excreted in stool.
CLINICAL MANIFESTATIONS
Schistosomiasis
Schistosomiasis denotes a complex of acute, or chronic infections with varying clinical manifestations at different stages. The clinical manifestations depend on the species of parasite, intensity of worm burden, and immunity of the person to the parasite. Cercarial skin penetration can result in local and temporary irritation and trigger a dermal rush, manifesting within hours and persisting for a couple of days as maculopapular lesions.
Katayama syndrome is a systemic hypersensitivity reaction that results from high quantities of antigens being released by migrating schistosomula, adult worms, or eggs, coupled with significant levels of circulating IgG. It may occur 2 to 12 weeks after a primary infection or a heavy reinfection. It occurs more frequently with S japonicum infections than the other schistosome species. Typically, the onset of Katayama syndrome is sudden, but symptoms are non-specific, including fever, headache, general malaise, and tiredness. Eosinophilia is usually present. Involvement of the lung can manifest with a dry cough, and can be seen radiologically as a patchy infiltrate.
Following infection, chronic symptoms evolve slowly, being due to inflammatory reactions to the eggs that are deposited in various organs. Symptoms vary depending upon the organism. The adult worms do not cause an immune reaction and are generally not the cause of symptoms. S haematobium infection causes granulomatous inflammation of the bladder wall, often causing ulceration resulting in both microscopic and macroscopic hematuria. Infection can cause substantial scarring, with ureteral obstruction. The damaged mucosal epithelium can undergo malignant changes, with squamous cell carcinomas. Fibrosis and bladder calcification are characteristic of late-stage infections and can eventually lead to parenchymal damage and kidney failure.11
S japonicum and S mansoni, infection is characterized by egg deposition in the intestine, particularly in the rectum and distal bowel. The mucosa may ulcerate. Typical symptoms include abdominal pain and (bloody) diarrhea.15Eggs often embolize through the portal vein to the liver where they cause a granulomatous hepatitis and marked fibrosis. Typically, portal hypertension develops. The liver disease may progress to cirrhosis and liver failure.11
Foodborne Trematodiasis
Infections with foodborne trematodes have a wide array of clinical signs and symptoms that are often non-specific. While light infections are in general asymptomatic, large parasite loads, prolonged durations of infection, hypersensitivity, or concomitant parasitic infections can cause considerable morbidity, and the diseases can even be fatal.
With regard to liver fluke infections, high fever, hepatitis-like symptoms and eosinophilia have been described for symptomatic O felineus infections.8 Symptomatic cases of clonorchiasis, fascioliasis, and infections with O viverrini are characterized by abdominal pain, flatulence, dyspepsia, anorexia, weakness, lassitude, weight loss, fever, rash, swollen abdomen, or enlargement of the liver. Jaundice, pruritus, and biliary colic are frequent complications of severe infections with Fasciola species.9 Ascending cholangitis, obstructive jaundice, and cholangiocarcinoma (bile duct cancer) are the most serious complication of clonorchiasis and opisthorchiasis.8,16
Clinical features due to an infection with the intestinal fluke F buski include abdominal pain, fever, nausea, diarrhea, constipation, eosinophilia, headache, dizziness, and malnutrition. Heavy infections are associated with generalized toxic and allergic symptoms such as edema of the face, abdominal wall, and lower extremities.9
Clinical symptoms of lung fluke infection include cough, fever, bloody sputum, loss of appetite, chest pain, and headache in the early stage of infection. Once the infection has been established, cough and bloody sputum are common.10 Extrapulmonary paragonimiasis is caused by migrating worms into ectopic locations, for example the skin, liver, eye, abdominal organs, or the brain. Cerebral paragonimiasis is particularly severe and can cause a variety of neurologic complications (headache, convulsions, paralysis, or behavioral changes).10
The pathologic changes of foodborne trematode infections are confined to the target organs of the adult flukes. The intestinal fluke F buski causes extensive duodenal and intestinal erosions, ulceration, hemorrhage, abscesses, and catarrhal inflammation.9 Pleural and pulmonary manifestations of paragonimiasis include multi-focal pleural hemorrhage, eosinophilic pleuritis, pleural effusion, pneumothorax, thickened pleura, peribronchiolar infiltration of lymphocytes and plasma cells, hyperplasia of bronchioles and peribronchiolar glands, and chronic active eosinophilic granulomatous pneumonia.10 In case of liver fluke infections, the bile duct, liver, and gallbladder are affected. In C sinensis and O viverrini infections, the biliary epithelium becomes edematous, often accompanied by periductal infiltrates of mononuclear cells. Metaplasia of the biliary cells into mucin-producing cells can lead to persistent and high mucus content of the bile. Desquamation of the biliary epithelium, epithelial hyperplasia, bile duct hyperplasia, and periductal fibrosis have been described in chronic infections.8 Finally, in the parynchymal phase of fascioliasis, mechanical destruction of the liver tissues, chronic ulceration, desquamation, and hemorrhage are caused by the migrating flukes. The mechanical liver damage is accompanied by a cellular inflammatory reaction by the host. Furthermore, factors produced or induced by the fluke as proteases might contribute to liver damage.
DIAGNOSIS
A number of different diagnostic approaches, referred to as direct parasitologic techniques (detection of parasite eggs in biological samples), indirect immunologic tests, molecular diagnosis, or noninvasive diagnostic techniques, are available for the diagnosis of schistosome, intestinal, liver, and lung fluke infections.
Schistosomiasis
The most widely used technique in epidemiologic surveys for diagnosis of S mansoni and S japonicum is the Kato-Katz technique, that is, microscopic examination, usually of approximately 42 mg of stool, prepared as a thick smear on a microscope slide. This technique is quantitative and allows infection intensity to be expressed as the number of schistosome eggs per gram of stool.18 Additionally, direct fecal smears (only a very small amount of stool is examined), sedimentation of fresh stool samples, or an ether-concentration method applied on preserved stool samples are used for subsequent examination under a microscope.18 A wide array of immunologic tests have been developed and widely used in China for large-scale population screening of S japonicum.19 For S haematobium, filtration of 10 mL of urine, preferably collected between 10 am and 2 pm (coinciding with maximal egg excretion rates) and subsequent microscopic examination is the most widely used method in epidemiologic surveys. This method is quantitative and infection intensity is expressed as the number of S haematobium eggs per 10 mL of urine. Reagent strip testing for detection of blood (microhematuria) and protein in urine (proteinuria) is also widely used and allows semiquantitative appraisal of infection intensity.18 A convenient method for appraisal of pathology due to schistosomiasis is ultrasonography for examination of the liver and bladder. It is mainly applied in hospital settings, but progress made with portable devices now allows using ultrasound in epidemiologic surveys.20
Foodborne Trematodiasis
Quantitative microscopic coprologic analyses (and sputum in the case of Paragonimus spp) are the most widely employed techniques for diagnosis of an infection with foodborne trematodes. Simple direct smears, simple sedimentation techniques, Kato-Katz thick smears, Stoll’s dilution egg count technique, or the formalin-ether concentration technique are used.8,12 However, multiple stool examinations are warranted to improve upon the diagnostic sensitivity. Serologic tests, mostly based on the detection of circulating antibodies, have been developed for the diagnosis of liver and lung fluke infections and have the advantage that they can be applied during all stages of the disease. Immunodiagnostic tests include intradermal tests, an indirect hemagglutination assay, an indirect fluorescent antibody test, and an indirect ELISA.8,10 Significant progress has been made in recent years regarding molecular methods, most notably the use of polymerase chain reaction–based (PCR-based) methods for the diagnosis of O viverrini, C sinensis, Paragonimus species, and F hepatica infections.8,10 Finally, noninvasive techniques to reveal pathologic alterations include radiology, ultrasound, computed tomography, or magnetic resonance imaging.
TREATMENT
There are two drugs currently recommended for the treatment of schistosomiasis and foodborne trematodiasis; namely praziquantel and triclabendazole (see Chapter 323 and Table 323-1).21-24
Praziquantel is the drug of choice for schistosomiasis, clonorchiasis, opisthorchiasis, paragonimiasis, and intestinal fluke infections in adults and children older than 2 years (in the case of schistosomiasis) and 4 years (in the case of foodborne trematodiasis).2,22 Triclabendazole is used against fascioliasis in patients aged 6 years and above.24
A third drug, bithionol, is still often used for fascioliasis and paragonimiasis if triclabendazole is not available, praziquantel failed to cure the infection, or patients displayed previous idiosyncratic or allergic reactions and praziquantel should not be given. Bithionol has been used in children below the age of 5 years.2 For schistosomiasis, oxamniquine has been widely and effectively used against S mansoni, particularly in Brazil.5 Metrifonate shows activity against S haematobium and has been widely used in the 1960s and 1970s, but due to economic, operational, and therapeutic reasons (eg, multiple doses are necessary to achieve good clinical outcomes), it has been suggested that schistosomiasis chemotherapy can do without this drug.5
PREVENTION
Preventive chemotherapy (eg, regular administration of praziquantel to at-risk populations without prior diagnosis) is increasingly promoted by WHO and other international organizations to limit the morbidity of schistosomiasis and foodborne trematodiasis.1,12,21 However, this strategy alone falls short of addressing the root behavioral and environmental causes of foodborne trematodiasis, schistosomiasis, and other often neglected tropical diseases. Sound information, education, and communication strategies to change human water contact behavior (in the case of schistosomiasis), to properly cook fish and other aquatic products, and to boil water (in the case of foodborne trematodiasis), as well as food safety measures and improved sanitary conditions, are key factors to achieve long-lasting effects on the control or even local elimination of foodborne trematodiasis and schistosomiasis.22,25 Linking preventive chemotherapy with health education and improved sanitary conditions, as well as collaboration with different sectors (eg, educational sectors or the food industry), will be required to ensure long-term parasite control and in turn boost social and economic development in areas where schistosomiasis and foodborne trematodiasis are still rampant.