Trematode Infections

Definition

Schistosomiasis, which is classified as a neglected tropical disease, is a parasitic infection caused by the trematode worms (blood flukes) of the genus Schistosoma. It has been reported in 78 countries worldwide, with 290 million people infected and nearly 800 million at high risk for infection. Mortality from schistosomiasis is estimated at 13,000 deaths per year, and the burden of disease at 3.3 million disability-adjusted life-years lost per year.

Epidemiology

Schistosomiasis occurs mainly in areas with poor sanitation in rural, periurban, and urban areas in endemic countries. The World Health Organization has set a goal of eliminating schistosomiasis by 2030, but schistosomiasis is still endemic in 78 countries. S. mansoni is found in the Arabian Peninsula, Egypt, Libya, Sudan, most countries in sub-Saharan Africa, Brazil, Suriname, and Venezuela. S. mansoni is found in Africa, South America (Brazil, Venezuela, and Surinam), and the Caribbean. S. haematobium is found in Africa and the Middle East, S. japonicum in China and the Philippines, S. intercalatum in West and Central Africa, S. mekongi in Southeast Asia, and S. guineensis in Cameroon, Equatorial Guinea, Gabon, and Sao Tomé.

The endemicity of schistosomiasis depends on the urban disposal of urine (S. haematobium) and feces (S. mansoni, S. japonicum, S. intercalatum, S. mekongi, S. guineensis), the presence of suitable snail hosts, and human exposure to cercariae. The freshwater snail intermediate hosts are Biomphalaria species in Africa and Biomphalaria glabrata (Australorbis) and Tropicarbis in South America and the West Indies. In some cases, the endemicity of schistosomiasis may be maintained by animal reservoirs. Such is the case with S. japonicum, which infects dogs and cows.

Etiology and Life Cycle

Adult worms live in the mesenteric veins ( S. mansoni , S. japonicum, S. mekongi, S. intercalatum, and S. guineensis ) or in the venous plexus around the lower ends of the ureters and the urinary bladder ( S. haematobium ) ( Fig. 326-1 ). In these sites, they start their sexual reproduction by releasing eggs. Once deposited in the host, eggs may stay in the mesenteric vein, be trapped in the intestines, escape to the intestinal lumen, and migrate by portal blood to the liver ( S. mansoni, S. japonicum; Fig. 326-2 ). Eggs of S. haematobium, which may be trapped in the intestines and bladder, may escape to the intestinal or bladder lumen. After being excreted with feces or urine into fresh water, the eggs hatch and release ciliated motile miracidia that penetrate into snails, which are the intermediate hosts. Following asexual multiplication in the snail, the development of cercariae, which are the infective forms for humans, requires 4 to 7 weeks. After leaving the snails, the cercariae can survive in fresh water for almost 72 hours. When penetration of the skin in the human host occurs, the cercariae lose their tails and change into schistosomula. Schistosomula migrate to the lungs and, in about 6 weeks, mature to adult worms that descend to their final habitat. Viable eggs can be seen in excretions (i.e., stool or urine) 5 to 9 weeks after cercarial penetration. The lifespan of the worms ranges from 5 to 10 years.

Pathobiology

Four main pathophysiologic mechanisms have been proposed in acute human schistosomiasis infection: a serum sickness-like hypersensitivity reaction ( Chapter 230 ), which is triggered by the deposition of eggs; a systemic hypersensitivity reaction against the migrating schistosomula and eggs; a toxemic and allergic reaction to the migrating and maturing larvae of Schistosoma, but not to eggs; and a more generalized systemic, immunologically mediated, Loeffler-like reaction, not specifically related either to larvae or to adult worms or to eggs.

In chronic schistosomiasis, tissue injury is mediated by egg-induced granulomas and the subsequent appearance of fibrosis. In S. haematobium, infected eggs induce the formation of granuloma in the urinary tract. Because the habitat of S. mansoni, S. japonicum, S. mekongi, S. guineensis, and S. intercalatum worms is the mesenteric blood vessels, the intestines are involved primarily, and egg embolism results in secondary involvement of the liver. Host genetics, immunologic response, and parasite load measured by egg count in the stool are associated with a greater chance for hepatosplenic involvement. Interleukin (IL)-4, IL-13, and IL-17 have been associated with granuloma formation and liver fibrosis. Enzymes and antigens released from eggs sensitize host lymphocytes, which migrate to areas of egg deposition and recruit other cell types, such as macrophages, eosinophils, and fibroblasts. The size of these granulomas and the resulting fibrosis lead to most of the characteristic chronic fibro-obstructive lesions in schistosomiasis. In the liver, the granulomas result in perisinusoidal obstruction of portal blood flow, portal hypertension, splenomegaly, esophageal varices, and portosystemic collateral circulation. Liver cell perfusion is not reduced; consequently, liver function test results remain normal for a long time.

In schistosome-infected populations, the intensity of infection increases during the first two decades of life as children accumulate worms, and then declines. Although exposure decreases with age, the lower intensities of infection in older individuals are due in part to acquired resistance. In the S. haematobium –infected population, immunoglobulin (Ig) E increases progressively with age, and IgE antibodies directed against adult worm antigens are associated with subsequent low intensities of reinfection. Similar associations between high IgE levels or a high IgE/IgG4 ratio and resistance to reinfection have been found among Brazilian and Kenyan subjects exposed to S. mansoni . In contrast, susceptibility to reinfection has been associated with IgG4, which may serve as blocking antibody that inhibits the action of IgE. A major codominant gene, called SM1, in the human host’s genome controls the intensity of infection by S. mansoni .

Modulation of the immune response is a characteristic of chronic schistosomiasis, and S. mansoni antigens downmodulate the immune response by increasing their production of regulatory cytokines such as IL-10 and the frequency of regulatory T cells. S. mansoni infection attenuates the clinical manifestations of type 1 diabetes and experimental autoimmune encephalitis in mice. In humans, S. mansoni attenuates the clinical manifestations of asthma and is inversely associated with the development of myelopathy related to human T-cell leukemia virus type 1 (HTLV-1) infection ( Chapter 360 ). S. mansoni infection may impair immunologic response to vaccines and change manifestations of other infectious diseases.

Clinical Manifestations

Clinical manifestations of schistosomiasis are divided into schistosome dermatitis, acute schistosomiasis, and chronic schistosomiasis. Schistosome dermatitis, or swimmer’s itch, is seen mainly when avian cercariae penetrate the skin and are destroyed. Schistosome dermatitis is a sensitization phenomenon that occurs in previously exposed persons. The cercariae evoke an acute inflammatory response with edema, early infiltration of neutrophils and lymphocytes, and later invasion of eosinophils. A pruritic papular rash occurs within 24 hours after the penetration of cercariae and reaches maximal intensity in 2 to 3 days.

Acute schistosomiasis occurs usually 20 to 50 days after primary exposure. Though asymptomatic in endemic areas, acute schistosomiasis is becoming a frequent and major clinical problem when nonimmune individuals from urban regions are exposed for the first time to a heavy infection in an endemic area. The clinical syndrome (i.e., fever, chills, liver and spleen enlargement, and marked eosinophilia) originally described for S. japonicum infection, and still common for this species, is increasingly being diagnosed in Brazil and Africa in individuals with S. mansoni infection. Malaise, diarrhea, weight loss, cough, dyspnea, chest pain, restrictive respiratory insufficiency, and pericarditis are also documented in this phase. Acute disease is not observed in individuals who live in endemic areas for schistosomiasis.

Diagnosis

Epidemiologic risk factors such as a history of contact with contaminated water and appropriate clinical manifestations are key to raise suspicion of schistosomiasis. About 50% of infected patients have eosinophilia. Liver enzymes and the serum bilirubin level are usually normal or mildly elevated. Anemia and thrombocytopenia may occur in severe chronic schistosomiasis. Hematuria is common in S. haematobium .

Molecular techniques to detect schistosoma DNA in stool, urine, and blood specimens have a high sensitivity for diagnosing acute infection and are very useful in returning travelers and in individuals who may have light infection. Quantification of circulating cathodic antigen (CCA) in urine also has a high sensitivity and can monitor the efficacy of antischistosome chemotherapy. A significant decrease in antigen levels is observed as early as 10 days after therapy. Serologic assays can detect antibodies to S. mansoni antigens but cannot distinguish between active and past exposure. As a result, they can be very useful for diagnostic purposes in travelers with suspected acute infection but not for residents in endemic areas.

Despite the appeal of these molecular and immunologic tests, examination of the stool for eggs is an essential part of the evaluation, and a definitive diagnosis still often requires finding schistosome eggs in stool, urine, or a biopsy specimen, usually from the rectum ( Table 326-1 ). ^, Because schistosome eggs may be few, concentration by sedimentation should be performed. All eggs from stools, urine, or tissues should be examined under high power to determine their viability by visualizing the activity of cilia of the excretory flame cells of the enclosed miracidium. Dead eggs may persist for a long time after successful therapy or natural death of the worms. The presence of only dead eggs does not necessarily require treatment. Because the intensity of infection is associated with morbidity, quantitative techniques are recommended. For S. mansoni and S. japonicum, the Kato-Katz thick smear method is used. In patients with chronic S. mansoni and S. japonicum infection and liver disease, the diagnosis is sometimes made by documentation of eggs in liver specimens. Ultrasonography allows determination of the degree of liver fibrosis. S. mekongi and S. intercalatum infections are diagnosed by examining the stool for eggs.

Urine examination for S. haematobium eggs can be performed by direct or concentration methods. Samples should be obtained at midday, when excretion of eggs is maximal. Assessment of urinary tract pathology by ultrasonography is recommended after the diagnosis is confirmed because of the increased incidence of carcinoma of the bladder ( Chapter 182 ).

Treatment

Prevention

Mass drug administration with praziquantel has been used as the mainstay of programs for the control and prevention of schistosomiasis morbidity, with school-based programs showing the most promising results. , However, this approach alone is not sufficient to eliminate or interrupt transmission of this disease. The development of anti- Schistosoma vaccines is necessary. Additional measures such as provision of clean water, use of molluscicides, adequate sanitation, and improvement of socioeconomic conditions also should be implemented to control the disease.