Chapter 49: Schistosomiasis

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Chapter 49: Schistosomiasis Amaya L. Bustinduy, MD MPH FRSTMH Department of Paediatrics Great Ormond Street Hospital for Children NHS Trust Great Ormond Street, London WC1N 3JH, UK Tel: +44 (0)20 7405 9200, Fax: +44 (0)20 7829 8643 Mobile: +44 (0) 7580 02 24 43 E-mail: [email protected]

and Charles H. King, MD MS FACP FRSTMH Center for Global Health and Diseases Case Western Reserve University School of Medicine 10900 Euclid Avenue Cleveland, Ohio 44106-7286, USA Tel: +1-216-368-3667 Fax: +1-216-368-4825 Mobile: +1-216-570-8135 e-mail: [email protected] Key Points: 

Schistosomiasis is a chronic inflammatory disorder that is initiated by infection with Schistosoma blood fluke parasites, and which causes tissue damage and systemic pathology that often persist into adulthood, even after infection abates.

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Anti-schistosomal, immune-mediated pathology is the primary cause of both systemic and organ-specific morbidity.

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Presentation of disease among long-term residents of Schistosoma-endemic areas differs from the disease presentation seen among travellers or migrants who have had only short-term exposure to the parasite.

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Transmission of Schistosoma spp. parasites requires specific intermediate host snails—human prevalence is closely tied to the abundance of suitable snail host species in local freshwater habitats.

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Poverty leads to a greater risk of Schistosoma infection as a consequence of

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inadequate sanitation and limited household access to clean water. 

New dams, irrigation, and urbanization can enhance local snail habitat and increase local transmission. This typically results in a dramatic increase in local prevalence of schistosomiasis.

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Diagnosis of active infection is established by detection of Schistosoma eggs in urine, stool, or tissue biopsies. Positive antigen testing and/or serology support the diagnosis in egg-negative cases

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Patient manifestations of schistosomiasis range from sub-clinical disease (including anaemia and growth retardation) to overt multisystem organ failure

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Praziquantel is the drug of choice for treating all forms of established Schistosoma infection

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Regular treatment with anti-schistosomal drugs decreases morbidity among affected endemic populations

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Full prevention of Schistosoma-related disease requires interruption of transmission in order to prevent early infection and rapid recurrence of infection during childhood.

EPIDEMIOLOGY

Schistosomiasis refers to human disease resulting from infection by any of the parasitic blood flukes of Schistosoma spp. Worldwide, it is estimated that over 239 million people are acute or chronically infected with one or more of these species, which are transmitted by specific aquatic or amphibious snails in a wide variety of freshwater habitats.(1) The various species of the genus Schistosoma are trematodes, members of the family Schistosomatidae, which are dioecious, digenean multicellular helminthic parasites, whose adult habitat is the vascular system of vertebrates (Figure 49.1). Of all the mammalian blood flukes, the genus Schistosoma has achieved the greatest geographical distribution and diversification (Figure 49.2).

(2)

Of the 16 species

of Schistosoma known to infect humans or animals, five are responsible for the vast majority of human infections. These are Schistosoma haematobium, S. intercalatum, S. mansoni, S. japonicum and S. mekongi. Very rarely, other zoophilic species or

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interspecies hybrid infections may be found in humans.

(2)

Because the parasite is transmitted via very specific intermediate-host freshwater snails, the perpetuation of the Schistosoma life cycle requires suitable environmental conditions as well as water contamination by human sewage.(3) Transmission is thus linked to local ecological factors as well as to underdevelopment and lack of sanitation. Persistent exposure to reinfection is tied to a lack of safe water sources for agricultural, domestic, and recreational activities,(4) a situation that is common throughout the developing world. As such, schistosomiasis is a preventable disease of poverty, with rising prevalence in rural areas and unplanned peri-urban developments.(5, 6) Infection may also be common in refugee camps where transmission is often difficult to control.(7) Prevalence estimates obtained from standard epidemiological surveys have been imprecise, because 20-30 per cent of infections are missed by standard egg detection assays performed on stool or urine specimens.(8-10) This misclassification has resulted in a considerable underestimation of the burden of schistosomiasis, and a biased view of how Schistosoma-related morbidity affects endemic communities.(11, 12) Early childhood serosurveys, combined with the use of antigen-detection diagnostic field tests, are now providing more refined estimates of age-specific prevalence in endemic areas.(13, 14) The 2011 estimated population at risk of schistosomiasis has increased to 779 million(1) based on changing demographics in endemic countries, and anthropogenic changes to the environment occurring via water project development. Based on systematic reviews, 106 million people in Africa are at high risk for schistosomiasis (both S. haematobium and S. mansoni) based on their living and working in proximity to large dam reservoirs or surface irrigation schemes.(15) In Asia, large hydroprojects such as the recently built Three Gorges Dam on the Yangtze river in central China, also have the potential to increase the prevalence of S. japonicum or S. mekongi infection by altering the river flow, local human population density, agricultural practices and their intermediate snail hosts’ habitat.(16) Until recently, descriptions of disease and disability related to Schistosoma infection have focused on the late, ‘pathognomonic’ complications of schistosomiasis. These advanced forms of schistosomiasis involve end-organ inflammation and fibrosis

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of the liver and portal venous system in intestinal schistosomiasis (caused by S. mansoni, S. japonicum, S. mekongi or S. intercalatum), and bladder, ureteral, and renal damage (caused by S. haematobium). However, based on population surveys, it is now appreciated that the occurrence of these end-organ complications is low (~10-20 per cent) relative to more subtle, but disabling chronic morbidities of Schistosoma infection,(17) including anaemia, growth stunting, cognitive impairment, and decreased physical fitness.(11, 12) During childhood in endemic areas, both prevalence and intensity of Schistosoma infection increase with age due to continuing exposure to high risk water bodies. This increasing infectious burden is associated with a parallel increase in morbidity due to the acute inflammation induced by the ~50% of parasite eggs that remain trapped in the body.(18, 19) Maximum egg excretion peaks between 12-15 years of age.(20) Intensity of infection typically decreases among older age groups, although for S. mansoni prevalence still tends to remains high for adults. This age-related change in infectious burden after adolescence is likely a multifactorial process,(21, 22) but debate continues about whether the apparent reduction of infectious burden in adult life Is related to acquired immunity, decreased exposure to contaminated water, or even decreased sensitivity of egg testing due to trapping of eggs in fibrotic tissue. The possibility of acquired anti-fecundity immunity, resulting in worms shedding fewer eggs, has also been advanced. In any event, local transmission is particularly favoured because children, who have the highest egg output in faeces or urine, are consistently more likely to be indiscriminate in terms of urination and defecation habits, thereby enhancing perpetuation of the local transmission cycle. Schistosoma eggs (Figure 49.3) have been found in the stool or urine of children as young as 2 years old, provoking questions about the true age of onset of disease caused by Schistosoma infection, particularly with regard to the age targets of current population-based control programmes, now focused on school age children (5-15 years of age).(23) More extensive studies will be needed to define this issue.(14, 24, 25)

Animal reservoirs Schistosoma japonicum is the only species having relevant animal reservoirs that

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contribute to environmental contamination through daily egg excretion (Figure 49.4). Thirty-one wild mammals and 13 domestic animals have been shown to carry S. japonicum in China,(26) and in the Philippines, cats, dogs, pigs, water buffaloes, and rats were found to have a 3 to 31% prevalence of viable S. japonicum eggs in the stool.(27) In hilly environments of China, where buffalo are less common, dogs appear to be the main zoonotic reservoir, with prevalence of up to 75 per cent.(28) In this setting, inclusion of animal infection prevention as part of schistosomiasis control campaigns has proven a more successful strategy in China.(29) In contrast, humans are effectively the only reservoir host of S. haematobium. The few infections with this parasite found among non-human primates, Arteriodactyla, or Rodentia can be considered as incidental and of no epidemiological importance. S. mansoni infections have been reported in a wide range of mammals (non-human primates, Insectivora, Arteriodactyla, Marsupilia, Rodentia, Carnivora, and Edentata). However, evidence implicating their role in maintenance of transmission of the parasite is, with two exceptions, lacking. In one focus in Tanzania, it is believed that baboons maintain the parasite among themselves,

(30)

and there is good reason to believe that

the local strain of S. mansoni is maintained by both rats (Rattus rattus – a known reservoir host) and by humans the a natural habitat of Guadeloupe Island (31, 32) and in some areas of Brazil. For S. mekongi in Cambodia, among local fauna, only dogs have been found to harbour parasite eggs in a recent survey.(33)

History S. haematobium Chronic haematuria and various bladder disorders were described in earliest recorded histories in association with the spread of agricultural civilization along the great river valleys of Egypt and Mesopotamia. Haematuria was described in the Gynaecological Papyrus of Kahun, written in the mid-XIIth dynasty, circa1900 BCE. Many remedies for haematuria were recorded in the Ebers Papyrus and it can be assumed that in that era the condition, presumably caused by S. haematobium, was widespread.

(34)

Calcified ova of the S. haematobium have been demonstrated in the

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kidneys of two Egyptian mummies of the XXth dynasty (1250– 1000 BCE).(35) During Napoleon’s invasion of Egypt (1799–1801 AD), symptoms of the disease were common among French troops.(36) However, it was not until 1851 that a causal agent (a blood fluke first called Distoma haematobium, now Schistosoma haematobium), was found by Theodor Bilharz during a post-mortem examination at the Kasr-el-Aini Hospital in Cairo.(37)

S. mansoni In 1902, Sir Patrick Manson found lateral spined eggs in the faeces of a colonial officer posted to the West Indies (then invalided to London) and postulated the existence of a second species of Schistosoma blood fluke parasites.(38) Subsequent controversy between A. Looss and L. W. Sambon, eminent scientists of the day, was resolved in 1915 by the work of Leiper at El Marg, a village in the present Qualyubia Governorate, just north of Cairo. Leiper established the existence of two distinct species of Schistosoma parasite and identified their transmission pathways via two different snail intermediate hosts belonging to two different genera and subfamilies.(39) In the New World, Schistosoma eggs with a lateral spine (S. mansoni) were identified both in Bahia State, Brazil in 1904

(40)

and in Venezuela in 1906.

(41)

S. japonicum In 1847, the clinical entities ‘Kabure itch’ and ‘Katayama syndrome’ were described in a village in the Hiroshima Prefecture in Japan

(42)

, while in 1904, Katsurada

(43)

recovered worms from the portal system of a cat and named the species Schistosomum japonicum. From 1909 to 1915, the biology of this parasite, its life cycle, and the pathology it causes were elucidated and described by Japanese and other investigators.(44) The species was recognized clinically both in China (45) and in the Philippines by the early years of the twentieth century

(46)

and in Sulawesi (Celebes) of

modern Indonesia in the 1930s.(47) Oncomelania intermediate host snails were identified in China in 1924 (48) and in the Philippines in 1932.(49)

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S. intercalatum In 1923 suspicion arose that, because some cases of human ‘intestinal’ schistosomiasis in the Yakusu area near Kisangani (in present-day Democratic Republic of Congo) showed an atypical clinical picture and possessed an unusual egg morphology, a species distinct from S. haematobium was involved.(50) Follow-up of this work led to a description in 1934 of a new species, S. intercalatum, for which the snail intermediate host was a member of the Bulinus africanus group.(51) The recent description of a new species of human schistosome, Schistosoma guineensis has led to a call for more extensive, DNA-based phylogenetic studies of the genus Schistosoma. This is work in progress currently suggests that S. intercalatum and S. guineensis should be treated as separate taxa closely related to S. haematobium.(52, 53)

S. mekongi and S. malayensis Initially described in 1978, S. mekongi causes human schistosomiasis in a restricted area of Laos and Cambodia.(54) Its intermediate host, Tricula aperta, is aquatic and is not susceptible to infection by S. japonicum.

(54, 55)

Another rare species from Malaysia,

S. malayensis, was identified in 1987 and found to be closely related to S. mekongi but genetically distinct. (56) S. malayensis is known to be a zoonotic disease with a vertebrate reservoir, Rattus muelleri (57) The intermediate vector is Robertsiella kaporensis, a triculinid snail.(58) To date, little is known about the clinical significance of S. malayensis. Geographic Distribution of Schistosomiasis According to the WHO, of the estimated 239 million people with schistosomiasis, the large majority (85 %) live in sub-Saharan Africa (Figure 49.2).(1, 59) Worldwide, Schistosoma infections are further distributed across three continents, and the disease is considered to be endemic in 74 countries.(1) Some previously affected nations, such as Tunisia and Morocco have recently interrupted transmission.(60) Intestinal schistosomiasis caused by S. mansoni is found in 54 countries, ranging from the Arabian Peninsula, across Africa, and in Madagascar. In South America, S. mansoni

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transmission still occurs at lower levels in Brazil and Venezuela and may persist in Surinam and several islands of the Caribbean.(61) (Worldwide distribution Map- Figure 49.2) S. haematobium is now endemic in 53 countries in the Middle East, the African continent and the Indian Ocean islands Madagascar, Zanzibar, and Pemba. In 40 countries, double infections with S. mansoni and S. haematobium are common.(62) S. intercalatum remains endemic in 10 countries in central and west Africa.(63) S. japonicum infection is found in mainland China, Indonesia (Lindu Lake valley and the Napu valley in central Sulawesi), and in certain islands of the Philippines. There is no evidence of recent transmission in Thailand or India, where an endemic focus in Gimvi village, state of Maharashtra, was still active two decades ago. Schistosomiasis was eradicated in Japan in the 1960s. S. mekongi is endemic on Khong Island, Lao People’s Democratic Republic, and in some areas of Cambodia.(64) Of the five most prevalent Schistosoma species, there are distinct differences in disease presentation based on the preferred localization of adult worms within the human body. S. mansoni, S. japonicum, S. intercalatum and S. mekongi generally prefer to inhabit the pericolonic venules of the portal venous system. All of these species produce ‘intestinal’ or ‘rectal’ schistosomiasis which may be further complicated by periportal fibrosis and portal vein hypertension as eggs become deposited in the liver via portal blood flow. By contrast, S. haematobium inhabits the terminal venules in the wall of the bladder, the genitourinary system, or the pelvic plexus within the distribution of the inferior vena cava, and it causes ‘genitourinary’ or ‘vesical’ schistosomiasis. S. haematobium eggs have a terminal spine, whereas eggs of S. mansoni are characterized by a laterally placed spine; those of S. japonicum and S. mekongi are smaller and are round or ovoid with a rudimentary spine (Figure 49.3). Egg shape does not appear to affect disease formation--Adult worms are relatively resistant to human host immune defences, while the majority of infection-related morbidity occurs as a consequence of host inflammatory responses directed against antigens released by parasite eggs that become embedded in host tissues. Neither S. haematobium nor S. mansoni is restricted exclusively to their preferred

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anatomical vascular habitats within the inferior vena caval or the portal venous systems. S. haematobium can exist in the perirectal venules and its eggs may be found in the stool. S. mansoni may live in the pelvic plexus and its eggs can be detected in urine (‘mansonuria’), although this is an uncommon finding during epidemiological surveys. Much less is known on human infection with S. intercalatum. Two geographical strains (‘Cameroon’ and ‘Zaire’) have been described,

(65)

having distinct intermediate

snail hosts and differing patterns of egg distribution within the host. Although S. intercalatum is a species distinct from S. haematobium, the two species appear to be closely related; like S. haematobium, S. intercalatum produces terminal-spined eggs of characteristic morphology. Natural hybridization has been described.(66, 67) Experimentally, in Erythrocebus patas monkeys, hybridization has also been reported between S. mansoni and S. intercalatum.

(68)

Infection by other Schistosoma species Infrequently, humans are infected by schistosomes that normally infect other mammalian hosts. For example S. bovis, a member of the S. haematobium complex and a common parasite in cattle and sheep, may occasionally infect humans. Likewise S. mattheei, which has multiple hosts in both domestic and wild animals in southern Africa, and S. margrebowiei, a parasite frequent in antelopes in central Africa, may possibly cause human infection.(69) Such infections in humans are seldom of pathological significance but suggestions have been advanced that they may confer a relative type of immunity (heterologous immunity) against S. mansoni and S. haematobium infections in areas where all species co-exist.(70) The cercariae of certain avian blood flukes, Trichobilharzia, Gigantobilharzia and Ornithobilharzia, may penetrate human skin producing cercarial dermatitis or ‘swimmer’s itch’. Outbreaks may occur in either tropical or temperate climates.(69, 71)

PATHOGENESIS AND PATHOLOGY (For detailed description of parasite morphology- see also Table 49.1)

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Adult Worms Unlike other trematodes, schistosomes are dioecious, having fully separate sexes in the adult stage, thus requiring both male and female infection of the same host in order to reproduce. However, an infecting population could conceivably be unisexual, with only male or female worms. This can be achieved under laboratory conditions, where a single miracidial snail infection is carried through to unisexual cercarial development and infections of only males or females.(72) In the setting of unisexual infection, worm development remains incomplete, suggesting that signalling between male and female partners helps to effect full worm maturation. Adult worms have a cylindrical body of 7 to 20 mm in length with two terminal suckers, an oral sucker opening to the alimentary tract, and a more posterior one used for attachment to the endothelium of blood vessels. Of great importance to worm survival in the milieu of the host’s bloodstream, schistosome adults have a unique heptalaminate tegument that protects the parasite against immunological attack, (73) The female surface is smooth whereas the male outer surface is covered with minute spines or tubercles in S. haematobium and S. mansoni, but not in S. japonicum, where the outer surface of the male is non-tuberculated (See Table 49.1).(72) Adult female worms are longer and thinner than males. Females are generally found paired with males, enclosed in the male’s ventral groove, the gynaecophoric canal. (Figure 49.1). The lifespan of the adult worm in humans is not accurately known. In the past, stress was laid on clinical evidence of longevity ranging from 18 years (74) up to 37 years, as reported in Madagascar migrant living in France.(75) Since the 1970s, epidemiological studies of the dynamics of egg output among groups of infected people (in the absence of treatment or in the absence of reinfection after successful treatment) have noted that a proportion of individuals cease to pass eggs in the excreta within a relatively short time. This has been interpreted as indicative of a shorter median mortality among established worm pairs and has led to current concept of the mean length of life of the female schistosome being of the order of 3–8 years.

(76, 77)

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Eggs Schistosoma eggs are spined, non-operculate, and contain an embryo, the miracidium, which develops inside the egg within a period of ~16 days. The speciesspecific morphologies (as explained earlier) are presented in Figure 49.3. Of note, not all eggs can effectively migrate from the venous circulation to the lumena of the bowel or bladder to effect their exit from the human host. As a rough generalization, approximately 50% of eggs ulcerate through the walls of the bladder or the colon, to be excreted in urine or faeces. Host immune-mediated inflammatory response is an essential part of this translocation. The remaining 50% are retained within the tissues. (78, 79)

These will die within 21 days of oviposition. Excreted eggs typically contain

embryos that can be seen to be viable by observation of flame cells, or of cilliary or whole-body movement on microscopy. In a suitable environment of fresh water and warmth (10–30ºC), the embryos (miracidia) hatch and leave the egg through slits induced partly by their own activity and partly by osmotic effects. An adult S. haematobium female produces 20–200 terminal-spined eggs/day, S. mansoni produces 100–300 or more lateral-spined eggs/female per day and S. japonicum produces 500– 3500 ovoid eggs with a rudimentary lateral ‘knob’/female per day. The fecundity of S. intercalatum (another terminal-spined species and of S. mekongi (ovoid eggs with a rudimentary lateral spine) are unknown. Miracidia On hatching from an egg in appropriate fresh water conditions, miracidia swim actively (at 2 mm/s), and home into snail secretions. They remain infective to snails for 8–12 h.(79, 80)

Intramolluscan development After contact, miracidia penetrate the body surface of the snail through a secretion from their apical gland cells; penetration is initiated by the papilla, the miracidial boring movement probably being assisted by lytic enzymes secreted from the gut.

(81)

After

penetration, the ciliated surface of the miracidium disappears and, in a suitable species of snail, a mother sporocyst will develop near the entry site. If the snail is not a potential

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host, miracidia are destroyed by phagocytic action of snail leucocytes. Only a small proportion of entering miracidia develop to mature mother sporocysts. (Figure 49.5) Over the next several weeks, the sporocyst develops germinal cells that, in turn, develop into daughter sporocysts that migrate into other parts of the snail’s body. After further development, each sporocyst can become a mature cercaria (Figure 49.6), which then is released from the snail. From a single miracidium, thousands of cercariae are formed as a result of this asexual multiplication process.(82, 83) A proportion of infected snails has a shortened lifespan or become sterile. Some exhibit self-cure and their egg-laying returns to normal. From the time of miracidial penetration, production of mature cercariae takes 4–5 weeks in the case of S. mansoni infection, 5–6 weeks for S. haematobium and 7 weeks or longer for S. japonicum. Numerous physical, environmental and biological factors account for these variations in maturation time.

Cercariae All cercariae originating from one miracidium are of the same sex; when mature, they emerge from the snail as a free-swimming stage adaptable to invasion of the definitive human host (Figures 49.6 and 49.7). Cercariae are furcocercous (brevifurcate), have no eye spots or pharynx, are