Schistosomiasis

SECTION 10  Helminthic Infections

52 

Schistosomiasis AMAYA L. BUSTINDUY  |  CHARLES H. KING

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. • Anti-schistosomal, immune-mediated pathology is the primary cause of both systemic and organ-specific morbidity. • 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. • 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. • Poverty leads to a greater risk of Schistosoma infection as a consequence of 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. • 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. • Patient manifestations of schistosomiasis range from sub-clinical disease (including anaemia and growth retardation) to overt multisystem organ failure. • Praziquantel is the drug of choice for treating all forms of established Schistosoma infection. • Regular treatment with anti-schistosomal drugs decreases morbidity among endemic populations. • 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 acutely or chronically infected with one or more of these species, 698

which are transmitted by specific aquatic or amphibious snails in a wide variety of freshwater habitats.1 However, some estimates suggest that more than 400 million people worldwide may be affected. 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 52.1). Of all the mammalian blood flukes, the genus Schistosoma has achieved the greatest geographical distribution and diversification (Figure 52.2).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 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% 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), due to 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



52  Schistosomiasis

Oral sucker Ventral sucker Ventral sucker Oral sucker Female Male

Gynaecophoric canal

Figure 52.1  Male and female schistosomes. (From Tropical Resources Unit: WHO.)

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 of the liver and portal venous system in intestinal schistosomiasis (caused by S. mansoni, S. japonicum, S. mekongi or S.

699

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%) 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 remain 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 52.3) 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

S. mansoni S. haematobium S. intercalatum S. japonicum S. mekongi Mixed S. hadematobium/S. mansoni Great rivers and lakes

Figure 52.2  Map of worldwide distribution of schistosomiasis. (From Gryseels B, Polman K, Clerinx J, et  al. Human schistosomiasis. Lancet 2006;368(9541):1106–18.)

700

SECTION 10  Helminthic Infections

150 120 90 60 30 0

A

B

C

D

E

Figure 52.3  Eggs from different Schistosoma parasites of humans (A) S. japonicum, (B) S. mekongi, (C) S. haematobium, (D) S. intercalatum, (E) S. mansoni.

infection, particularly with regard to the age targets of current population-based control programmes, now focused on schoolage 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 contribute to environmental contamination through daily egg excretion (Figure 52.4). A total of 31 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 3–31% 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%.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 in the natural habitat of Guadeloupe Island31,32 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

Figure 52.4  Animal reservoirs of Schistosoma japonicum in Hunan province, China: these buffalo used by villagers in their farm activities serve as local reservoirs for Schistosoma japonicum parasites, which helps to perpetuate local transmission. (From WHO/TDR/Crump.)

S. haematobium Chronic haematuria and various bladder disorders were described in the 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 midXIIth dynasty, circa 1900  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 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 190440 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, Katsurada43 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 China45 and in the Philippines by the early years of the twentieth century46 and in Sulawesi (Celebes) of modern Indonesia in the 1930s.47 Oncomelania intermediate host snails were identified in China in 192448 and in the Philippines in 1932.49 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 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

52  Schistosomiasis

701

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 subSaharan Africa (Figure 52.2).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 transmission still occurs at somewhat lower levels in Brazil and Venezuela and may persist in Surinam and several islands of the Caribbean (Figure 52.2).61 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 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.65 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.66 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.65,67

Pathogenesis and Pathology For a detailed description of parasite morphology, see Table 52.1.

Life Cycle The Schistosoma transmission cycle is complex and highly efficient when the right environmental conditions are met (Figure

702 TABLE 52.1 

SECTION 10  Helminthic Infections

Comparison of Principal Features of Schistosoma spp. Parasites Infecting Humans S. mansoni

S. japonicum

S. haematobium

S. intercalatum

S. mekongi a

Location of adult in host Posterior gut caecum

Mesenteric veins Very long

Mesenteric veins Medium

Vesical plexus Short

Mesenteric veins Short

Mesenteric veins Medium

MALE Length (mm) Width (mm) No. of testes Tubercles

6–13 1.10 4–13 (6–9)b Coarse

10–20 0.55 6–7 Absent

10–15 0.90 4–5 Fine

11–14 0.3–0.4 2–7 (4–5)b Fine

115 0.41 6–7 Absent?

FEMALE Length (mm) Width (mm) Ovary: position in body Uterus: position in body Length No. of eggs

10–20 0.16 Front third Front half Very short 1–2

20–30 0.30 Middle Front half Short 50–200

16–26 0.25 Rear third Front two-thirds Long 10–50

10–14 0.15–0.18 Rear half Front two-thirds Long 5–60

112 0.23 Rear half Front half Short 10+

Ovoid 61 × 140 Lateral Faeces 100–300 +ve

Round 60 × 100 Lateral (reduced) Faeces 3500 +ve

Ovoid 62 × 150 Terminal Urine 20–300 −ve

Ovoid 61 × 176 Terminal Faeces (and urine) 150–400 +ve

Round 57 × 66 Lateral (reduced) Faeces ? ?

Adult Worms

Mature Egg Shape Size (µm) Spine Normally passed in Eggs/female per day Reaction of egg shell to Ziehl–Neelsen stainc a

From experimental animal infections. Usual range. c In histological sections. Courtesy of Sturrock RF, Department of Medical Parasitology, London School of Hygiene and Tropical Medicine. Reproduced with permission from Jordan P, Webbe G, Sturrock RF, editors. Human Schistosomiasis. Wallingford: CAB International; 1993. b

52.5).68 All species have a common pathway from sexual reproduction by adult schistosomes within the vascular system of the definitive human host, an asexual phase in the freshwater intermediate snail host and a return to the human via cercarial invasion of the skin or mucosa on a host’s exposure to cercariainfested water. Adult schistosomes are dioecious, with full separate sexes. They live as pairs within capillary blood vessels (Figure 52.6), in different anatomic locations depending on the species: S. mansoni, S. japonicum, S. mekongi and S. intercalatum in the mesenteric veins and S. haematobium in the vesical plexus. The slender and smooth females are held in the gynaecophoric canal of the male, where they copulate (Figure 52.1). 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 years69 up to 37 years, as reported in a Madagascar migrant living in France.70 However, the average worm lifespan is estimated to be 3–5 years.71 The females produce non-operculated eggs daily throughout their lives, with varying numbers depending on the species. The position of the terminal spine varies among species as shown in Figure 52.3. The miracidium, or inside embryo, will develop within a period of ~16 days. About 50% of eggs laid by the female worms are excreted into the stool or urine by ulcerating through the wall of the bowel (S. mansoni, S. japonicum, S. mekongi, S. intercalatum) or bladder, ureteral and genital mucosa (S. haematobium). The remaining 50% induce an acute and chronic inflammatory response in the host tissues that will trigger granuloma

formation leading to scarring, local damage and organ dysfunction.72 Eggs may also embolize from their initial intravascular origin to liver, lung and many other sites.73 When viable schistosome eggs are excreted and reach fresh water, either by direct deposition or by being washed in from a neighbouring site, in a suitable environment of warmth and light the larva within each egg becomes active and aided by osmosis the egg ruptures or ‘hatches’; the larva, now termed a miracidium, emerges. Miracidia are mobile organisms swimming actively by means of ciliary movements. Miracidial behaviour is related in a general way to the ecology of the snail intermediate host and adaptive behavioural patterns have been described. On hatching from an egg in appropriate fresh water conditions, miracidia swim actively (at 2 mm/s) towards snail secretions. They remain infective to snails for 8–12 h.74,75 Miracidia then penetrate the soft tissues of the snail, influenced by numerous variables, including chemotaxis, the relative number of larvae and snails within a water body, length of contact time and physical characteristics of the surrounding medium, i.e. water temperature, velocity of flow, turbulence and the presence of ultraviolet light. Only a small proportion of entering miracidia develop to mature mother sporocysts. 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, which then is released from the snail. From a single miracidium, thousands



52  Schistosomiasis

Male Female Larvae mature in the liver

703

Larvae migrate to the left heart and into circulation

Worms mature and pair off

Chronic schistosomiasis Worms migrate to mesenteric vessels of bowel or bladder where females lay eggs Larvae migrate first to the lungs through venous circulation

Eggs retained in tissue Cercariae become schistosomata Eggs excreted in faeces or urine

Cercariae penetrate skin

Cercariae released into fresh water

Fresh water

S. haematobium

Bulinus species

S. mansoni

Biomphalaria species

S. japonicum

Oncomelania species

Ova

Miracidia hatch

Miracidia develop into sporocysts and produce cercariae

Miracidia penetrate intermediate host (snails)

Figure 52.5  Schistosoma life cycle. (From King CH. Toward the elimination of schistosomiasis. N Engl J Med 2009;360(2):106–9.)

of cercariae are formed as a result of this asexual multiplication process.76,77 Free-swimming fork-tailed cercariae, <1 cm in length, penetrate human skin or mucosa when a person is exposed to infested water (Figure 52.7). For S. haematobium and S. mansoni the main stimulus for the release of cercariae is light, usually at temperatures between 10°C and 30°C. Cercarial lifespan is short: 36–48  h, as they are non-feeding organisms dependent on their large glycogen reserves. Throughout their long life, snails continue to produce a reasonably constant output of

cercariae; many thousands can originate from a single miracidium. Cercariae become schistosomules as they penetrate human skin and lose their tail (Figure 52.8). There is a remarkable transition from a ‘freshwater environment’ to a ‘saltwater environment’ as the larva moves into the human body through the tissues, lymphatics and venules making repeated circuits of the pulmonary–systemic circulation before entering a blood vessel leading to the hepatic portal system and transform into male and female adult worms.

704

SECTION 10  Helminthic Infections

Figure 52.6  Adult Schistosoma mansoni in the portal circulation. The figure shows a cross-section of a male and female S. mansoni in a branch of the portal vein (H&E, ×44). (From Peters W, Pasvol G. Atlas of Tropical Medicine and Parasitology, Copyright © 2006, with permission from Elsevier.)

Figure 52.9  Intermediate hosts of Schistosoma mansoni are various species of Biomphalaria freshwater snails (×4). (From Peters W, Pasvol G. Atlas of Tropical Medicine and Parasitology. Copyright © 2006, with permission from Elsevier.)

Pairing of male and female schistosomes takes place on sexual maturity, with subsequent migration to the preferred sites of egg deposition.

Intermediate Hosts The biology of the intermediate snail hosts (Figures 52.9–52.11) of the schistosomes is a complex subject covered in specialist texts to which reference should be made for specific details. Although the schistosomes and their intermediate hosts can be divided roughly into groups reflecting their zoogeographical distribution and host specificity, the situation is complicated because the distribution of schistosomes does not exactly match that of the potential intermediate hosts.78 INTERMEDIATE HOSTS OF S. HAEMATOBIUM Figure 52.7  Schistosoma haematobium cercaria as seen on differential interference contrast microscopy. (From WHO/TDR/Stammers.)

S. haematobium is transmitted by some 30 nominal species of the genus Bulinus, classified into four species-groups: Bulinus

Figure 52.8  Cercarial penetration of the skin. (From O.D. Standen.)

Figure 52.10  Intermediate hosts of Schistosoma haematobium are freshwater bulinid species within the Bulinus africanus complex (×3.5). (From Peters W, Pasvol G. Atlas of Tropical Medicine and Parasitology. Copyright © 2006, with permission from Elsevier.)



52  Schistosomiasis

705

lakes; the B. alexandrina group has a scattered distribution in Africa and is common in the Sudan and Egypt. B. sudanica has both east and west African species components. In the Americas, the genus Biomphalaria is represented by some 20 species but, of these, only B. glabrata (Say), B. straminea (Dunker) and B. tenagophila (Orbigny) have been found to be naturally infected with S. mansoni. INTERMEDIATE HOSTS OF S. JAPONICUM AND S. MEKONGI

Figure 52.11  Oncomelania: intermediate snail host of Schistosoma japonicum (×3). (From Peters W, Pasvol G. Atlas of Tropical Medicine and Parasitology. Copyright © 2006, with permission from Elsevier.)

africanus, an important group medically as species within the group, namely Bulinus nasutus and B. globosus (Figure 52.10),79,80 are intermediate hosts of S. haematobium in Africa south of the Sahara and, additionally, some cattle schistosomes; the B. forskalli group is distributed in a pan-African fashion with representatives found in Arabia and in some Indian Ocean islands; the B. truncatus/tropicus complex, again of pan-African distribution, extends from Malawi to east, west and north Africa and the Middle East as far as Iran; a small group, B. reticulatus is found patchily in Africa (e.g. in Ethiopia) and in isolated habitats in the Arabian peninsula. INTERMEDIATE HOSTS OF S. INTERCALATUM Of the two biologically distinct strains of S. intercalatum known to exist, one is transmitted by snails of the Bulinus africanus group and occurs in a restricted area of north-east Zaire; the other is transmitted by B. forskalli and occurs in Cameroon and Gabon. Each strain is unable to develop in a snail with which the other is compatible and, additionally, there are differences in prepatent periods and in certain enzyme patterns of the parasite. INTERMEDIATE HOSTS OF S. MANSONI S. mansoni is transmitted by snail species of the genus Biomphalaria (Figure 52.9), which is widely distributed throughout Africa, the Nile valley and the Arabian Peninsula, but not in Iraq or Iran. In the Americas, the genus is found in the southern USA, several Caribbean islands (notably Puerto Rico, St Lucia, Guadeloupe and the Dominican Republic) and on the South American continent in Brazil, Surinam and Venezuela. The framework for the taxonomic status was described in 1978,81 and four species-groups are still recognized. The Biomphalaria pfeifferi group has several forms and is found in all parts of Africa south of the Sahara, the Malagasy Republic, in Aden, Yemen and Saudi Arabia; the B. choanomphala group has only a few forms restricted to certain of the great natural African

S. japonicum is transmitted by amphibious snails, populations of polytypic Oncomelania hupensis (Figure 52.11), of which there are six subspecies: O. h. hupensis in mainland China; O. h. quadrasi in the Philippines; O. h. nosophora in Japan; O. h. lindoensis in Sulawesi, Indonesia; and O. h. formosana and O. h. chiui in Taiwan, where schistosomiasis is confined to animals and does not exist in humans. A genus Tricula aperta from the subfamily Triculinae transmits S. mekongi. The Oncomelania shell differs markedly in size and shape from those of the aquatic snails and Oncomelania snails have very different biological characteristics. In the Philippines, the average longevity is 66 days but in other endemic areas they may survive for 12 months or longer and may tolerate cold temperatures down to 0°C.82–84 AESTIVATION Both aquatic and amphibious snails have the capacity to survive out of water for weeks, or in some cases, for months; this phenomenon – ‘aestivation’ – has important consequences on the epidemiology of the infection and its control; immature infections of both S. mansoni and S. haematobium can be carried through from one wet season to another, thus perpetuating the transmission cycle. PARASITE–INTERMEDIATE HOST RELATIONSHIPS If we pair a very complex parasite–intermediate host relationship with anthropogenic changes in the distribution and abundance of snails hosting schistosomes,15,84 it becomes apparent that more detailed research in malacology must be undertaken to fully understand snail biology and the parasite–snail interaction.85 Both environmental and genetic factors play a role in the transmission of schistosomes through particular species of snails. While snail control was a mainstay of schistosomiasis control programmes in the first part of the twentieth century, it was not particularly successful in stopping transmission in many areas. It is clear that a better understanding of snail biology and ecology is needed to provide better inputs for programmes aiming to limit transmission on the intermediate host side. The genera Bulinus and Biomphalaria are aquatic snails found in many different habitats including permanent or semipermanent small ponds, marshes, swamps, rivers and streams and large permanent water bodies such as lakes, dams, irrigation channels and rice fields. Their biology varies with their environment and comprehensive studies are required to elucidate the details of snail survival and the factors leading to successful Schistosoma transmission. Cross-fertilization is usual in aquatic snails, but they are in fact hermaphrodites and capable of self-fertilization. Ova are laid in water as egg masses some

706

SECTION 10  Helminthic Infections

5–10 mm in diameter. Hatching of free-living snails occurs in 1–2 weeks; a steady growth ensues and maximal size and maturity is seen in 3–6 months. Like mosquitoes, snail intermediate hosts have an enormous reproductive potential because egglaying continues throughout life and life spans have wide variations in the different species; e.g. Bulinus globosus infected with S. haematobium have lived for 400 days in captivity and Biomphalaria pfeifferi infected with S. mansoni have survived for 213 days.78,86

Pathogenesis and Pathology THE ROLE OF HOST IMMUNITY Primary Infection In endemic areas, schistosomiasis infection occurs as early as infancy, when young children are exposed to contaminated water in bathing and playing (Figure 52.12).24,25 Serosurveys indicate that significant exposure occurs by 3.5–4.5 years of age.14,87 However, symptomatic acute schistosomiasis (Katayama syndrome) is seldom seen among children frequently exposed to S. mansoni or S. haematobium, possibly due to in utero imprinting of T- and B-cell responses, which has been identified among babies born to parasitized mothers.88 In acute schistosomiasis among short-term travellers and migrants not previously exposed to Schistosoma infection, patients express a considerably higher in vitro cellular response to parasite antigens than do comparable patients from endemic areas having chronic schistosomiasis. This is especially true for egg antigens. IgM and IgG against a carbohydrate epitope with the surface of larval schistosomes (KLH) is found in greater quantities in the serum of acutely exposed individuals, with a mixed Th1 and Th2 cytokine response to parasite antigens in the acute phase.89,90 Studies in experimental animal models have long suggested that there is significant down modulation of immune responses to schistosome antigens as infection persists and exposure to egg antigens becomes chronic.91,92 While this downregulation of immune response, with a shift

Figure 52.12  Mothers with young children do their family washing at a pond near their home. The water contains intermediate host snails for Schistosoma haematobium and both parent and child are significantly exposed to infection. (From WHO/TDR/Crump.)

towards Th2 type immune responses, may reduce the risk of morbidity caused by chronic inflammation, it is not clear if this experience-related immunity provides protection against new infections. Chronic Infection and Reinfection After the primary infection in childhood, reinfection occurs regularly during subsequent years, with only limited resistance apparent at this stage of early childhood (ages 5–11). As schistosomes do not replicate within the body, it is this process of repeated exposure that results in progressive acquisition of higher worm loads, manifested by high parasite egg burdens, along with resultant pathology and morbidity. However, it is well known from community-based surveys that the prevalence and intensity of infection progressively decrease in the teenage years (>12 years) and that in successive decades of adulthood, there is a decline in egg output, suggesting a further spontaneous decline of infection intensity to much lower levels.3,93 There is strong evidence that disease formation is a consequence of the inflammatory immune activation that occurs during Schistosoma infection.19,92 Careful studies of reinfection after successful cure have associated increased production of inflammatory cytokines IL-6, C-reactive protein and TNFα with systemic morbidities such as anaemia and growth impairment.94–97 The pathways leading to anaemia are multifactorial, including splenic sequestration, iron loss and ‘anaemia of chronic inflammation’. Chronic inflammation stimulates production of IL-6 that in turn increases the production of hepcidin, a liver hormone that regulates iron homeostasis. The downstream cascade leads to ‘iron trapping’ in the body storage sites, blocking its normal release and usage for haemoglobin production.96,98 The immune responses to chronic infection appear to vary during the course of disease progression. There are recognizable differences between those individuals without fibrosis, those with incipient fibrosis and those with recognized hepatosplenic disease. Those with early stages of fibrosis have an increased IgG (particularly IgG4) response to soluble egg antigens (SEA), while those with established hepatosplenic disease express higher levels of immune response to soluble worm antigen preparation (SWAP).89 In studies of cellular immune response, there is a predominantly Th2 anti-parasite response in chronic schistosomiasis that has been associated with hepatic fibrosis particularly among males94 and production of cytokine IL-13 (as modified by IL-5) has been correlated with individual levels of fibrotic disease.89 An interesting observation in helminthic immunology and in particular that pertaining to S. haematobium, is the dramatic increase in the production of parasite-specific and non-specific IgE, which is typically associated with allergic responses (atopy) among patients in the developed world. However, in the case of parasitic infection, it has been postulated that IgE can, in fact, provide a beneficial protective effect.99 Concomitant immunity, in experimental terms, describes the resistance, partial or total, of an actively infected host to a subsequent challenge infection by the same type of organism. Adult worms evade the immune responses by adding a layer of host-specific antigens to their tegumental membranes. Adult worms of a primary infection are unharmed by cercarial challenge but the invading forms of the challenge infection tend to be destroyed. Concomitant immunity likely occurs to schistosome infections in many experimental hosts and in humans.100

Further exploratory progress was made through longitudinal field studies involving detailed quantification of egg outputs and water contact in children, allied to the technique of reinfection studies. Chemotherapy is given to remove existing infections; the levels of newly acquired infections (reinfections) are observed, quantified and related to water contact and degree of exposure. These techniques produced strong evidence that age-dependent resistance to reinfection is distinct from agedependent exposure change in two areas, The Gambia and Kenya, for both S. haematobium and S. mansoni infection. For example, in The Gambia, changes in intensity of infection with time were compared in two communities, in one of which transmission had been interrupted by mollusciciding. In this area, the mean lifespan of the worms was 3–4 years, allowing comparison with the untreated area (control) of the numbers of eggs deposited by worms over the same 3-year period. The acquisition of new infections by adults over 25 years of age was 1000-fold less than that of 5–8-year-old children. This difference could not be attributed to a 1000-fold reduction of water contact in the adults, thus suggesting age-dependent acquisition of immunity to superinfection.101–105 Thus, the role of immunity in limiting schistosome infections in communities in two areas endemic for S. haematobium and S. mansoni was placed on a firmer footing. However, the immunity is probably not absolute, is evident only after years of exposure to infection and some data suggest that it occurs earlier in areas of high prevalence and intensity. The balance of the immune response in the early years of exposure to infection is directed towards production of blocking antibodies, which may be of IgM, IgG or IgG4. Protective antibodies, IgE or other immunoglobulin isotypes, are detected in both older children and adults who appear to be relatively resistant to infection.104 Later data led to surmise that ‘resistance’ to acquired infection, or reinfection after successful chemotherapy, is multifactorial and compartmentalized. It may involve both humoral and cellular responses at different stages of parasitic invasion. Known influencing variables are an IgE response, high levels of interferon γ (IFNγ) and tumour necrosis factor α (TNFα) and peripheral blood mononuclear cell (PBMC) responses involving different groups of cells and various cytokines, allied to a possible genetic factor on chromosome 5q31–q33.106,107 Impact of Infection on Vaccine Response Recent studies suggest a decreased response to vaccines in children born to mothers infected with schistosomiasis and other endemic helminthic parasites.108 For children vaccinated against tuberculosis with the Bacillus Calmette-Guerin (BCG), it has been found that purified protein derivative-driven T cell IFN-γ production, evaluated 10–14 months after BCG vaccination, was significantly lower for infants who experienced prenatal sensitization to schistosomes in utero, relative to subjects who had not been sensitized.109 These findings suggest important public health implications with respect to vaccination campaign efficacy in schistosomiasis-endemic areas.108 PATHOLOGY The pathology resulting from Schistosoma infection is overwhelmingly due to the egg-induced inflammatory response (Figure 52.13). Adult worms are impervious to the immune system of the host and by themselves cause little or no

52  Schistosomiasis

707

Figure 52.13  The fibrotic granuloma around this dead ovum in the colon is known as a Hoeppli reaction (H&E, ×70). (From Peters W, Pasvol G. Atlas of Tropical Medicine and Parasitology. Copyright © 2006, with permission from Elsevier.)

pathology, although they excrete antigens such as the gutassociated soluble antigens found in the sera of patients with schistosomiasis and which are now used both as a marker for infection and as an indicator of therapeutic success.110 Host inflammation is essential to the reproductive success of the parasite – schistosome eggs cannot traverse capillary beds unaided because they measure up to 70  µm in width. Slightly fewer than half of the eggs laid into host venules are able to ulcerate (via host inflammatory reaction) into the lumen of the gut or urinary tract and so leave the human body. The remainder are retained in the walls of these organs or are embolized into the portal radicles or lung arterioles. Collateral vascular bypasses enable eggs to reach many other organs in the body. At oviposition, eggs are immature, but miracidial maturation takes place within a few days. Soluble egg antigens (SEAs) originating from the secretory glands of miracidia enclosed within eggs diffuse out through submicroscopic pores in the eggshell and induce a host hypersensitivity response. The immunopathology of schistosomiasis is considered to be due to granuloma formation around tissue-deposited eggs and is a manifestation of delayed hypersensitivity through a T-cellmediated immune response.19 The florid granuloma is composed of the schistosome egg surrounded by cellular aggregates of eosinophils, mononuclear phagocytes, lymphocytes, neutrophils, plasma and fibroblasts (Figure 52.13). Activated macrophages cluster close to the eggshell, while lymphocytes and plasma cells are peripherally placed. Fibroblasts appear early and throughout the lengthy involution process, replace other cell types. Many granulomas are of sizes much greater than those of schistosome eggs, reducing in size as the infection shifts from acute to chronic after 3 months. There are consistent and strong correlations of high organ and tissue egg loads and severe pathology in quantitative autopsy studies in S. haematobium and S. mansoni.111 Other factors may operate, such as direct and indirect fibroblastic proliferation and induced abnormalities of types I and III collagen. Independent of infection intensity, individual variation in the intensity and context of host immune response may also affect the severity of tissue damage.92

708

SECTION 10  Helminthic Infections

Unlike early ‘acute’ granulomas, the late, obstructive and fibrous lesions of advanced chronic schistosomiasis respond poorly to antischistosomal chemotherapy.19 Antibody and cellular immune response specific to each stage of infection are long-lived and persist after successful chemotherapy.112 The inflammation and fibrotic injury schistosomiasis can persist long after a successful ‘cure’ of Schistosoma infection. As such, schistosomiasis should be seen as the preventable, chronic inflammatory condition caused by present or previous infection with metazoan parasitic blood flukes of Schistosoma species. The disease case definition then becomes: a person who has, or has previously had, infection with Schistosoma spp. parasites. The pathophysiology of schistosomiasis varies within stages of the life cycle as presented below. The differences among them are clearer in non-immune affected people such as visitors, tourists, or immigrants who become infected for the first time following a defined, brief exposure in endemic areas. Cercarial Invasion and Schistosomular Migration Cercarial invasion of the skin or mucosal penetration on exposure to infested water, particularly when the local level of transmission is high, can occur in <15 min; the clinical consequence of cercarial dermal invasion is a cercarial dermatitis lasting for some 24–48 h.113 The first pathophysiological response to invasion is the initiation of marked eosinophilia and an antibodydependent cell-mediated cytotoxic response to schistosomula involving IgG.114 Katayama syndrome, or ‘acute toxaemic schistosomiasis’, is a clinical entity that appears between 14–84 days in non-immune individuals exposed to schistosome infection. It resembles serum sickness, presenting as a hypersensitivity reaction to the migrating schistosomulum and to early egg deposition by maturing female worms. In and around areas endemic for S. japonicum, epidemics of Katayama syndrome have been reported in communities affected by large-scale flooding (Figure 52.14).115 Schistosome Maturation and Egg Deposition At variable times after infection, from some 2 months onwards, the stage of established infection occurs, with continuous

Figure 52.14  ‘Katayama syndrome’ manifesting as massive giant urticaria soon after infection with S. mansoni. (From Peters W, Pasvol G. Atlas of Tropical Medicine and Parasitology. Copyright © 2006, with permission from Elsevier.)

egg-laying associated with the ‘classical’ symptoms and signs of established schistosomiasis. SEAs from miracidia in the eggs provoke a T lymphocyte-mediated host response, which, in time, results in the characteristic granuloma with eosinophils prominent in the destruction of the eggs. Established Infection with Continuous Egg-laying After some years, changes in clinical symptoms and physical signs appear and there is superimposition of late-stage complications such as obstructive uropathy, genital bleeding and inflammation, hydronephrosis and pyelonephritic renal failure in S. haematobium infection, or portal hypertension which may be ‘compensated’ or ‘decompensated’ with ascites and hepatosplenomegaly with or without gastrointestinal bleeding in S. mansoni, S. japonicum and S. mekongi infections. Modulation by T suppressor lymphocytes and antibody blockade diminish the host immune response over time with a more prominent Th2 response;89 fibroblasts stimulate collagen production and fibrotic complications involving a variety of anatomical sites (e.g. periportal hepatic fibrosis and obstructive uropathy) ensue. PATHOLOGY OF CHRONIC INFECTION Because of differences in the Schistosoma species’ preferred anatomic localization, many of the ‘classic’ manifestations of chronic schistosomiasis are species-dependent. However, all forms of schistosomiasis cause similar levels of chronic inflammation and so share common aspects of systemic morbidity that include anaemia and impaired growth and cognitive development.12 Schistosoma Haematobium Urinary Bladder.  The urinary bladder is the most frequently affected organ in schistosomiasis haematobia. Cystoscopy, surgery, or autopsy reveal the gross lesions, which are often multiple.73 A hyperaemic mucosa is universal on cystoscopy.116 ‘Sandy patches’ occur in one-third; these are raised greyishyellow mucosal irregularities associated with heavy egg deposition and surrounded by dense fibrous tissue. Calcifications often occur in advanced cases. These are most commonly sighted at the trigone and near the ureteric orifices. Other raised lesions found in the urinary and nearby genital tracts are granulomas, nodules and polyps, which may be sessile or pedunculated and are related to local heavy tissue egg loads.18 Vesical ulcers are less common and can vary in size from a small irregular defect to an irregular deep transverse fissure. These occur mainly on the posterior wall of the bladder. Ureters.  Classic post-mortem studies have shown that though the ureters are less frequently affected than the bladder, their involvement is important for it leads to morbidity and is the forerunner of obstructive uropathy.73 Tissue egg loads in the ureters are greater in cases with obstructive uropathy than in those without. Bilateral ureteric involvement is the rule. The histopathological appearance of the ureteric lesions resembles that of bladder lesions and granulomatous lesions resolve and lead to ureteral fibrotic stenosis.19 Rising back pressure leads to hydroureter, with or without hydronephrosis, causing obstructive uropathy (Figure 52.15). This may predispose to chronic or recurrent infections by enteric bacteria, including Salmonella.117



52  Schistosomiasis

709

Schistosomal antigens have been observed by immunofluorescent microscopy in mesangial areas of the glomeruli in uncomplicated cases of S. haematobium infection. Granular deposits of IgG, IgM and C3 have also been noted, yet with a lack of basement membrane changes, an absence of clinical renal disease and with maintenance of normal renal function.123 There remains doubt about whether S. haematobium causes a specific nephritis given the presence of other potential mechanisms of renal failure.124 A reversible nephrotic syndrome in S. haematobium complicated by Salmonella infection has been described.125 Lung.  Pulmonary arteritis and cor pulmonale are rare in pure S. haematobium infection, yet egg granulomas are frequently encountered in the lung at autopsy.19

Figure 52.15  Renal contrast radiograph showing bilateral hydronephrosis in chronic urogenital schistosomiasis. (From Peters W, Pasvol G. Atlas of Tropical Medicine and Parasitology. Copyright © 2006, with permission from Elsevier.)

Genital Organs.  Because S. haematobium parasitizes the vesical plexus, eggs are often found in both male and female genital organs.73 In males, the mean S. haematobium egg count/g of seminal vesicle tissue was 20 000 in one investigation.18 The resultant enlargement, muscular hypertrophy and fibrosis produced an increase in weight of the seminal vesicles that correlated with the presence of obstructive uropathy. Much less commonly affected were the prostate, testes, epididymis and penis. Haematospermia is often a presenting symptom of genitourinary schistosomiasis. Orchitis, prostatitis, dyspareunia and oligospermia have been associated with male genital schistosomiasis and have been shown to resolve after antischistosomal therapy.118,119 In females, the finding of eggs in the female genital organs is similarly frequent; eggs may be found in the vulva, vagina or cervix, where friable polypoid or nodular lesions and sandy patches may be seen (Figure 52.16).120 Nodules in the perianal skin are not rare. The internal female genital organs – ovaries, Fallopian tubes and uterus – are much less commonly affected. However, pelvic schistosomiasis can cause reversible and irreversible female infertility.121,122 Female genital schistosomiasis is increasingly recognized as a co-morbid condition with HIV/ AIDS in sub-Saharan Africa. Gastrointestinal Tract.  S. haematobium eggs are found frequently in the gastrointestinal tract, their density being highest in the appendix with a decreased density in the distal tract. Polyps have been recorded in the rectosigmoid colon in an autopsy study of S. haematobium cases; the polyps were inflammatory and were often ulcerated.18 S. haematobium eggs are often seen in rectal biopsy material, but are usually dead. Kidney.  Although schistosomal granulomas are rare in the kidney parenchyma, renal lesions occur as a sequel of obstructive uropathy and are most often manifest as pyelonephritis.

Ectopic Lesions.  Migration of S. haematobium within the vascular system and subsequent egg-laying may produce a variety of ‘ectopic’ or atypical lesions. For example, mirroring the disease caused by S. mansoni and S. japonicum (agents of intestinal schistosomiasis), low-grade liver periportal fibrosis has been detected by ultrasonography in patients with S. haematobium infection.126 The finding of eggs of S. haematobium in the CNS, although not as common as seen in S. japonicum or S. mansoni infection, seem to have few clinical sequelae; eggs appear to produce minimal or no histological reaction, in contrast to the production of inflammatory response when eggs are laid elsewhere in the body. The spinal cord is affected more often than the brain.127 Rare anatomic localization of parasite lesions has been described, such as multiple S. haematobium egg deposition in the pericardium causing a fibrous pericarditis,128 and the demonstration of an adult S. haematobium worm in the choroid plexus.129 Bladder Cancer.  The exact mechanism of bilharzial bladder carcinogenesis remains unknown. However, squamous cell

Figure 52.16  Female genital schistosomiasis: Homogenous sandy patches and abnormal blood vessels on the uterine cervix of a woman infected with Schistosoma haematobium. Long arrows, convoluted blood vessels; short arrows, homogenous yellow sandy patches; Os, uterine os. Some superficial sandy patches are seen next to the os. (From Kjetland EF, Ndhlovu PD, Mduluza T, et al. Simple clinical manifestations of genital Schistosoma haematobium infection in rural Zimbabwean women. Am J Trop Med Hyg 2005 Mar;72(3):311–19.)

710

SECTION 10  Helminthic Infections

bladder cancer associated with S. haematobium infection remains a major cause of morbidity in many countries. In the past, it was the most commonly diagnosed cancer of Egyptian men from parasite-endemic areas, who experienced up to 10 times the incidence of bladder cancer compared with men from non-endemic countries. The WHO International Agency for Research on Cancer has found sufficient evidence to consider S. haematobium a carcinogen.130 S. haematobium-related tumours may be differentiated from non-bilharzial tumours by their younger age of onset, a greater male-to-female ratio and by their pathology and clinical presentation. S. haematobium-associated tumours tend to be multifocal squamous cell cancers, as compared with the transitional cell tumours common in Europe and North America. Such bladder tumours have been successfully induced in animals (monkeys and baboons) exposed to S. haematobium infection.131–133 One hypothesis postulates that the decades-long presence of chronic inflammation in the bladder facilitates DNA damage and the development of multi-centric cancers of the bladder wall. Co-factors for carcinogenesis include chronic bacterial infections and exposure to chemical carcinogens (petrochemicals, dietary nitrosamines). Raised urinary levels of β-glucuronidase related to chronic pyuria may ‘retoxify’ previously glucuronidated (i.e. detoxified) excreted carcinogenic chemicals, facilitating induction of bladder cancer in the presence of S. haematobium.134,135 In Iraq, coastal Kenya, Ghana, Malawi, Mozambique, Zambia and Zimbabwe, there is a consistent association between the local prevalence of S. haematobium infection and bladder carcinoma. However, in Nigeria, South Africa and Saudi Arabia, all countries with a moderate or high prevalence of S. haematobium, the association is not present. Whether this difference is due to strain differences in the parasite or to local differences in exposure to carcinogenic co-factors is not known. Most squamous cell cancers in schistosomal bladders are fairly well-differentiated, largely indolent and localized, spreading directly through the bladder wall with late and infrequent lymphatic spread. Bloodstream metastasis is rare. This picture contrasts sharply with that of transitional cell carcinoma. Largescale, population-based anti-schistosomal drug therapy directed at the control of morbidity would be expected to lower cancer incidence rates in the affected endemic countries and studies to this end are in place in Egypt. The critical problem will be the acquisition of accurate and acceptable population-based incidence estimates of bladder cancer. Schistosoma mansoni In schistosomiasis mansoni a range of chronic lesions is found, from scattered granulomas of the intestinal tract to gross hepatic periportal fibrosis (Symmer’s pipe-stem fibrosis; bilharzial claypipe stem fibrosis) (Figure 52.17). Because of varying localization of the mature S. mansoni worms, focal granulomas and fibrosis may occur in any part of the intestinal tract, but these are found most frequently in the rectosigmoid colon because the preferred habitat of adult S. mansoni is in the tributaries of the inferior mesenteric vein. These lesions can lead to clinical symptoms of diarrhoea, haematochezia and abdominal pain. Pathology in the small bowel is not as severe as that in the large gut. In late-stage infections, particularly in Egypt and Brazil, autopsy studies suggest a shift in egg deposition from the colon to the small intestine.136

Figure 52.17  Periportal fibrosis (‘pipestem fibrosis’) is the classic pathological hepatic lesion of intestinal schistosomiasis. (From Peters W, Pasvol G. Atlas of Tropical Medicine and Parasitology. Copyright © 2006, with permission from Elsevier.)

Colonic polyposis (Figure 52.18), a syndrome often found in Egypt, occurs in younger patients and is related directly to their intensity of infection. The colon and rectum are the sites of multiple pedunculated polyps with associated mucosal swelling, hyperaemia and oedema. The concentration of eggs within the polyps is much higher than at other sites in the intestine. The clinical accompaniments are significant blood and protein losses producing anaemia, chronic diarrhoea, tenesmus and a protein-losing enteropathy. Occasionally pseudotumours of schistosomal eggs surrounded by extensive fibrous tissue occur in S. mansoni infection and are termed ‘bilharziomas’. Sites of predilection are the omentum, mesenteric lymph nodes, paracaecal region and infrequently the wall of the gut. Rarely, reports appear in the literature relating intestinal obstruction caused by chronic schistosomal infection.136

Figure 52.18  Massive S. mansoni-associated polyposis of the colon, with fatal intestinal haemorrhage, seen at post-mortem of an Egyptian farmer. (From Peters W, Pasvol G. Atlas of Tropical Medicine and Parasitology. Copyright © 2006, with permission from Elsevier.)



52  Schistosomiasis

711

hepatic capillary network.138 Hepatic fibrosis results from the accumulation of collagen and may originate in the proliferation of collagen-synthesizing cells, increased synthesis by existing cells or deficiency in collagen degradation.139,140 In experimental animals, the amount of collagen in the liver increases in parallel with egg granuloma formation. In human hepatic schistosomiasis, there is increased collagen content and marked collagen synthesis in wedge liver biopsy material when compared with control tissue. The natural course of pure periportal fibrosis is slow and is termed ‘compensated’ because liver cell function tests show only slight abnormalities, if any. Over time, the consequences of portal hypertension with splenomegaly and/or variceal haemorrhage, with or without ascites, appear, although hepatic decompensation does not develop until an advanced stage of the process. However, in countries where there is a high prevalence of viral hepatitis (hepatitis B, C, D or E), these may co-exist with hepatosplenic schistosomiasis and the clinical progression of decompensated hepatic fibrosis presents a much more rapid progress because hepatocellular pathology is much more severe than in the state of hepatic fibrosis due to Schistosoma infection alone.

Figure 52.19  Eggs of S. mansoni in liver tissue, stained with H&E. (From CDC, Images courtesy of Dr. Munaf Desai, Al Qassini Hospital, Shatjah, United Arab Emirates.)

Hepatosplenic Schistosomiasis The major pathognomonic complication of chronic S. mansoni infection is periportal hepatic fibrosis. Because the basic pathology is sited in and around the portal tracts (Figure 52.19) and the hepatic parenchyma remains normal in uncomplicated cases, the term cirrhosis is inappropriate for Schistosomarelated liver disease. A cut section of the liver, which may or may not be enlarged, shows macroscopic, wide bands of fibrosis around portal tracts, resembling the stems of a number of clay pipes (Figure 52.17). The surface of the liver may be smooth, granular or nodular. Between portal fields, the hepatic parenchyma specifically does not exhibit the nodularity of Laënnec’s cirrhosis. Deposited eggs produce granulomas with surrounding inflammatory infiltrates in the connective tissue that surrounds the hepatic veins, proximal to presinusoidal vessels. Affected portal tracts become blocked with granulomas and disorganized by inflammation, fibrosis and pyelophlebitis.137 Eggs surrounded by an eosinophilic infiltrate, schistosomal pigment and/or organizing thrombi are found. The accumulation of granulomas around sites of blockage leads to further portal enlargement and simultaneously, the hepatic arteries enlarge and push out new branching capillaries. Thus the presinusoidal portal hypertension produces a compensatory arterial flow. Total intrahepatic blood flow remains within normal limits, with maintenance of hepatocellular metabolic function. The diminished portal blood flow from portal hypertension is compensated for by the increase in hepatic arterial supply and the rich capillary arterial network around the portal branches, which communicates with the portal vein.137 There remain unexplained discrepancies between clinical and pathological interpretations of the arterial origin of the

Spleen.  Splenomegaly is the usual accompaniment of hepatic schistosomiasis and is due to portal venous hypertension, chronic passive congestion and reticuloendothelial hyperplasia. Focal infarcts and trabecular haemorrhages may occur and the spleen is tough and fibrotic. Hypersplenism may produce pancytopenia or leucoerythroblastic anaemia. The spleen may become enormously enlarged (Egyptian splenomegaly or Banti’s syndrome in the older literature), as in kala-azar (visceral leishmaniasis) or the myeloproliferative syndromes. Gamna-gandy bodies (organized foci of bleeding within the spleen caused by portal hypertension) have been found in patients with hepatosplenic schistosomiasis.141 Lymphomas have been occasionally associated with schistosomal splenomegaly.142 Lungs and Heart.  Pulmonary hypertension, caused by granulomatous pulmonary arteritis originating from large-scale embolization of eggs, is commonly the result of established hepatic fibrosis with extensive portocaval shunting, as occurs with chronic S. mansoni or S. japonicum infection.136 Granulomatous inflammation occludes distal pulmonary arterial branches and eventually produces a rise in pulmonary arterial pressure with right ventricular hypertrophy and strain; the smaller arterioles show fibrointimal sclerosis; fibrinoid necrosis and angiomatoid formation is widespread in alveolar tissue. This complication arises in long-standing cases of heavy infection and presents clinically as congestive heart failure arising in chronic cor pulmonale. Kidney.  Renal lesions, known as schistosomal nephropathy (or glomerulonephritis), occur in S. mansoni infection. These consist of deposition of immune complexes of host immunoglobulins with adult worm or egg antigens in the glomerular mesangium and basement membrane. A variety of glomerular lesions has been found at autopsy in hepatosplenic patients. Mild proteinuria is common in S. mansoni infection and in hepatosplenic cases, progressive nephropathy leading to renal failure occurs in a small proportion of patients, although the clinical course is slow and the risks are greater from the hepatic complications.136 Amyloidosis has been demonstrated in renal

712

SECTION 10  Helminthic Infections

biopsy material from patients with the nephrotic syndrome and schistosomiasis in Egypt.143 Egg deposition in the kidney is rare and is not thought to be responsible for serious renal dysfunction. Central Nervous System.  ‘Cerebral’ schistosomiasis has traditionally been associated with S. japonicum infection, but eggs of S. mansoni have also been found in the brain. The route of infection is thought to be via Batson’s valveless intervertebral plexus or by arterial egg embolism. Eggs may be present in the CNS with little or no histological reaction and, in a randomly selected series of hepatosplenic cases of schistosomiasis coming to autopsy, one-quarter of patients had S. mansoni eggs in the brain;144 these cases may be minimally symptomatic. Myelopathy with various motor and/or sensory presentations occurs, more commonly in S. mansoni than in S. haematobium infection and cord compression or infarction with resulting paraparesis has been well described in the literature. Not infrequently, spinal cord schistosomiasis is recognized as part of the acute toxaemic syndrome that occurs in tourists and transient visitors to endemic areas.145 Other Ectopic Lesions.  Cutaneous lesions due to S. mansoni are rare, although papular or nodular lesions at different sites are known. In Egypt, genital lesions are commonly found at autopsy. Placental schistosomiasis has been reported from Brazil.146 Cancer.  According to the WHO, despite the number of case reports linking S. mansoni infection and different types of cancer, namely colorectal cancer, liver cancer and giant follicular lymphoma, there is inadequate evidence in humans for the carcinogenicity of infection with Schistosoma mansoni.130 Schistosoma japonicum The intestinal and hepatic lesions of S. japonicum are, in general, similar to those occurring in S. mansoni infection, but with several specific differences. The primary lesion is a T cellmediated granuloma formed around parasite eggs, but modulation of the granuloma size may be antibody- and T cellmediated, whereas in S. mansoni infection cell mediation is the dominant mechanism. The adult worms are located in the branches of the inferior mesenteric vein and in the superior haemorrhoidal vein.147 An adult female deposits 1000–3500 eggs/day, with the highest density found in the large intestine and, in descending order, in the rectum, sigmoid and descending colon (Figure 52.20). The small intestine is relatively lightly affected. Knowledge of the pathological anatomy (gross and microscopic) of S. japonicum lags behind that of S. mansoni infection because autopsy studies are fewer. Advanced schistosomiasis japonica has also been progressively declining as a cause of death for some decades.136,148,149 Gastrointestinal Disease.  In experimental animals, gastrointestinal lesions of S. japonicum infection are focal and isolated and are interspersed with normal bowel. Segmental lesions occur in humans and multiple lesions are common including mucosal hyperplasia, pseudopolyposis, ulceration and thickening of the intestinal wall. Gastric schistosomiasis is seen frequently in surgical or biopsy specimens. Subclinical cases are

Figure 52.20  Eggs of Schistosoma japonicum in wall of colon (H&E, ×150). (From Peters W, Pasvol G. Atlas of Tropical Medicine and Parasitology. Copyright © 2006, with permission from Elsevier.)

probably common but go unrecognized owing to non-specific symptomatology and relatively insensitive diagnostic techniques for detection of S. japonicum infection.8 Hepatosplenic Disease.  Macroscopic hepatic changes in chronic schistosomiasis japonica parallel those in S. mansoni infection. The liver is frequently enlarged with an irregular surface. On cross-section, the characteristic wide bands of fibrous tissue surrounding the larger portal tracts are seen and Symmer’s periportal (clay-pipe stem) fibrosis is found at autopsy (Figure 52.17). Microscopically, the picture is one of chronic pseudotubercles with chronic inflammation, cellular infiltrates around eggs, extensive fibrosis and neovascularization in the portal tracts. The accompanying manifestations of portal hypertension (i.e. splenomegaly with or without gastrointestinal varices, with or without bleeding) are common in advanced disease. Central Nervous System.  In contrast to S. mansoni and S. haematobium infections, the brain is more commonly affected in S. japonicum infection, although spinal cord involvement appears to be less frequent. The cerebral lesions are caused either by intracranial egg deposition or by egg embolism via a vascular route. Lung.  While cor pulmonale does occur in schistosomiasis japonica, there are fewer reports in S. japonicum infection than in S. mansoni infection, despite the similar pathogenic mechanisms.136 Cancer.  Epidemiological studies have not demonstrated any direct relationships between gastric cancer and S. japonicum infection and the WHO-IARC has not found sufficient evidence to declare S. japonicum a human carcinogen.130,136 Schistosoma mekongi Although the clinical manifestations of S. mekongi infection are similar to those of S. japonicum, the morbidity and pathology resulting from the former are compounded by the presence of Opisthorchis viverrini in areas endemic for S. mekongi. Objective descriptions of detailed pathology in humans are lacking.



52  Schistosomiasis

Schistosoma intercalatum and S. guineensis The distribution of S. intercalatum is restricted to 10 countries in central and West Africa and more information exists on experimental infection than on human infection. However, the pathology of S. intercalatum infection is known to be primarily due to inflammation of the sigmoid and rectum.150 On proctoscopy of hospital inpatients, the rectal and colonic mucosa were considered abnormal in 47 out of 85 patients. Nonspecific lesions predominated: mucosal congestion, oedema, bleeding and/or ulceration. In liver biopsies, granulomatous lesions, of a size smaller than those seen in S. mansoni infection, were seen in the portal tracts. Tissue reaction to eggs was slight or absent in some patients. No portal hypertension was seen.150,151 The newly described S. guineensis, the only schistosome species on the island of Sao Tome, has been shown to produce ‘pipestem-type’ hepatic portal septal fibrosis and genital involvement. Other pathological sequelae are currently under investigation. It is suspected that hybridization with S. intercalatum occurs. The parasite is susceptible to treatment with pra­ ziquantel but may require increased dosage or courses of chemotherapy.53

Clinical Features GENERAL PRESENTATION OF SCHISTOSOMIASIS In the past, textbook descriptions of schistosomiasis have focused just on Schistosoma infection-specific pathologies and their associated symptoms. However, these ‘pathognomonic’

TABLE 52.2 

713

findings prove to be only a limited portion of the disease spectrum associated with schistosomiasis; we now know that such classical descriptions of schistosomiasis reflect only a minority (<10%) of patients. Not surprisingly, many Schistosoma-infected patients have ‘nonspecific’ symptoms caused by the chronic granulomatous pathology from parasite egg deposition in their tissues. There is increasing recognition of the more prevalent, but less dramatic, disabling conditions associated with chronic schistosomiasis including anaemia, growth retardation, decreased physical performance, poor school performance and sub-optimal work productivity.11,12,152,153 Furthermore, there is now better understanding that, in terms of patient morbidity and disability, schistosomiasis is a chronic inflammatory condition that is initiated by infection with Schistosoma parasites and which causes damage that persists even after infection abates.154,155 Syndromes Common to All Schistosome Infections For a detailed description of syndromes common to all schistosome infections, see Table 52.2. Cercarial Dermatitis.  Cercarial dermatitis occurs most commonly upon exposure to avian cercariae, with human cases reported both in schistosomiasis-endemic and non-endemic countries.67,156,157 Itching (pruritus) of the skin is the primary symptom, arising within a few minutes of exposure and receding within 24–72  h, accompanied in some cases by erythema and/or a papular eruption.113 The condition can occur after exposure to any of the five Schistosoma spp. that commonly infect humans and affects mostly non-immune visitors.

Summary of Schistosoma spp. Infections of Humans, Their Impact on Health and Their Recommended Drug Treatment

Schistosoma spp.

Transmission

Geographic Distribution

Clinical Presentation

Treatment

Schistosoma mansoni

Through skin in fresh water contaminated by feces; Intermediate host: freshwater Biomphalaria snail

Africa; Middle East; Caribbean; Latin America

Praziquantel 40 mg/kg/day PO for 1 day

Schistosoma haematobium

Through skin in fresh water contaminated by urine; Intermediate host: freshwater Bulinus snail

Africa; Middle East

Schistosoma japonicum

Through skin in fresh water contaminated by feces; Intermediate host: freshwater Oncomelania snail

China; South-east Asia; Philippines

Schistosoma mekongi

Through skin in fresh water contaminated by feces; Intermediate host: freshwater Trichula snail

South-east Asia

Schistosoma intercalatum

Through skin in fresh water contaminated by feces; Intermediate host: freshwater Bulinus snail

Central and West Africa

Acute: Abdominal pain, wasting, anaemia Chronic: Growth retardation, anaemia, grand mal epilepsy ascites, portal hypertension. transverse myelitis Acute: Haematuria, dysuria, wasting, anaemia Chronic: Growth retardation, anaemia, decreased fitness, impaired cognition, renal failure, hydroureter/ hydronephrosis, dyspareunia, infertility, bladder carcinoma Acute: Abdominal pain, anaemia Chronic: Growth retardation, anaemia. grand mal epilepsy, ascites, portal hypertension, transverse myelitis Acute: Abdominal pain, anaemia Chronic: Growth retardation, anaemia, grand mal epilepsy, ascites, portal hypertension. Acute: Abdominal pain, wasting, anaemia Chronic: Growth retardation, anaemia, ascites, portal hypertension.

Praziquantel 40 mg/kg/day PO for 1 day

Praziquantel 60 mg/kg/day divided tid PO for 1 day

Praziquantel 60 mg/kg/day divided tid PO for 1 day Praziquantel 40 mg/kg/day PO for 1 day

714

SECTION 10  Helminthic Infections

Acute Schistosomiasis.  This acute illness can be found after exposure to any of the schistosomes infecting humans, but it is most marked in primary infections among non-immune individuals with S. japonicum infection. Also termed acute toxaemic schistosomiasis, it is also known as Katayama syndrome, or Katayama fever, after the Katayama region in Hiroshima prefecture, Japan, where it was originally described. Where Schistosoma transmission is coming under partial control, Katayama syndrome can also affect residents of endemic areas (Figure 52.14). In China, for example, rebound epidemics have typically been reported in endemic communities exposed to floods.115 Acute schistosomiasis is much less commonly reported for S. haematobium infection and there are no data on its occurrence with S. intercalatum or S. mekongi infection. The incubation period of acute schistosomiasis varies between 14–84 days after individuals are exposed (either to a first schistosome infection or to heavy reinfection) and symptoms are often nonspecific. This frequently poses a diagnostic challenge to the clinician. The multiple clinical manifestations are related to schistosomal migration and to early egg deposition, presenting with a constellation of systemic symptoms including nocturnal fever, non-productive cough (with diffuse pulmonary infiltrates found on radiography), myalgia, eosinophilia, headache and abdominal pain. Almost all cases have a history of water exposure.114 Serum anti-Schistosoma antibodies suggest the diagnosis and schistosome egg excretion, if detected, will substantiate the presence of infection.158 If the initial presentation includes neurological symptoms or spinal cord syndromes, this is an indication for urgent investigation and therapeutic intervention. Systemic Effects of Established Infections For a detailed description of systemic effects of established infections, see Table 52.2. Anaemia.  Community-based surveys in Schistosoma-endemic areas have frequently demonstrated associations between infection and anaemia12,159 at both high- and low-level parasitic loads, suggesting mixed aetiologies. Iron deficiency is more commonly associated with heavy infection and is likely due to enteric blood losses in the face of poor dietary iron intake.96 Importantly, anaemia of chronic inflammation has also been documented in schistosomiasis. The mechanism is believed to be ‘iron trapping’ related to persistent inflammation, the production of pro-inflammatory IL-6 and an associated release of hepcidin, a liver hormone responsible for decreased iron availability.160 Increases in other pro-inflammatory cytokines, C-reactive protein (CRP) and TNFα, have also been associated with Schistosoma-induced anaemia. This has been best studied in S. japonicum-endemic areas.96,98,161 Decreased Physical Performance.  Decreased aerobic capacity (an impaired ability to deliver oxygen to the tissues) has also been reported in epidemiological surveys in Schistosomaendemic areas.152 This deficit, or related reduction in physical work output, is highly correlated with anaemia and malnutrition in patients with schistosomiasis.152,162 GROWTH RETARDATION There is a relationship between childhood schistosomiasis and undernutrition (growth stunting and wasting) that is becoming

more clearly defined.17 Schistosoma infection-related malnutrition hinders children from attaining their full growth potential if they are not treated before linear growth stops at the end of puberty.163 Both acute and chronic malnutrition have been associated with schistosomiasis, most frequently with S. japonicum, but also with S. mansoni and S. haematobium.12,98,164–166 Dramatic weight improvements have been seen in Kenya after a single therapeutic dose of praziquantel, with greatest improvements seen in children who were more severely affected at baseline.167 Boys have frequently been found to be more affected by the nutritional complications of Schistosoma infection than girls.168 Cognitive Delays Significant associations have been found between S. japonicum infection and reduced scores on tests of intellectual function among school-age children.161 After adjustment for nutritional status, socioeconomic status (SES), haemoglobin, sex and the presence of other helminths, children with S. japonicum infection were specifically found to have reduced scores in tests of learning. Randomized, placebo-controlled praziquantel treatment studies for S. japonicum have likewise shown a treatment-related improvement in fluency, recall and visual search ability.169 Similarly, heavy S. haematobium infection among Tanzanian children has been associated with poor performance in standardized tests of verbal short-term memory and reaction time,170 and S. mansoni infection has been associated with poor IQ performance on Wechsler Intelligence testing in Egypt.171 Disability The 1996 WHO-World Bank Global Burden of Disease Project attributed a very low disability weight to schistosomiasis (0.5%), based on that era’s flawed perception that most people with current or past Schistosoma infection were ‘asymptomatic’ and only patients with advanced disease were seriously ill. As a result of this error, the Disability-Adjusted Life Year (DALY) estimates for schistosomiasis proved to be unrealistically low.11,12,155 Inaccurate notions about schistosomiasis were based, in part, on results of earlier case–control studies of symptoms and work productivity that compared ‘infected’ versus ‘uninfected’ persons living in Schistosoma-endemic communities. We have since come to appreciate the significant insensitivity of standard parasitological testing for Schistosoma infection,8–10 a phenomenon that caused significant misclassification of infection status in these earlier studies, resulting in significant bias against detection of relevant infection-related symptoms. Inaccuracies also affected many drug treatment trials: The treatment effect of anti-schistosomal therapy was most often gauged based on the outcomes of single-round treatment of overt chronic infections. The observed effects of ‘causal therapy’ were often minimal or temporary, leading to the false impression that treatment of the ‘average’ case of schistosomiasis had only minimal impact on human health. Subsequent recognition of the long-term, ‘subtle’ morbidities of schistosomiasis, i.e. undernutrition, growth stunting and cognitive impairment, has led to a reassessment of the lifetime impact of chronic or recurrent infection in Schistosoma-endemic areas.12 These sequelae are the cumulative result of long-term inflammatory illness and are slow to resolve. Single-treatment regimens were unlikely to reverse these pathologies immediately, nor were the benefits of therapy likely to be durable if

reinfection occurred rapidly,163,172,173 as is the norm in endemic transmission zones.174 Finally, because disease caused by Schistosoma infection persists after infection abates, duration of chronic ‘schistosomiasis’ (i.e. the disease triggered by Schistosoma infection) must be viewed in terms of decades of associated morbidity. From this perspective, there is nothing ‘asymptomatic’ or ‘benign’ about the average case of schistosomiasis and its disabling impact is substantially greater than the published estimates currently in use by global health planners.175 LOCALIZED AND ORGAN-SPECIFIC EFFECTS Genitourinary Schistosomiasis (S. haematobium) – Common Features For genitourinary schistosomiasis, the cardinal complaint is recurrent haematuria. Other urinary tract symptoms may precede or be associated, for instance burning on micturition, frequency, suprapubic discomfort or pain. Bladder involvement may lead to precipitancy, dribbling or incontinence. In fact, in an endemic area, any urinary tract symptom is an indication to explore for the presence of S. haematobium. However, in many countries in Africa, in the young age groups and early teenagers, macroscopic haematuria may be virtually universal; in boys it provokes little comment and may be regarded as a natural sign of puberty. In the phase of established chronic infection, it is common to recognize two stages: (1) a more active stage of disease development in children, adolescents and young adult patients, with egg deposition in many organs and egg excretion in the urine with proteinuria and haematuria, macroscopic or microscopic and (2) in older patients, where urinary egg excretion is sparse or absent but extensive pathology has developed.176 Chronic bladder lesions may produce persistent urinary dribbling and occasionally multiple fistulas in the perineum, with the picture of the ‘watering-can scrotum’; this is also seen in areas of heavy transmission in children and young teenagers where exposure is maximal, but the phenomenon is much rarer nowadays than in the past, coincidental with the more widespread use of chemotherapy. Surveys have shown wide regional variation in co-existent bacteruria; when present, the predominant organisms are E. coli, Klebsiella spp., Pseudomonas spp. and Salmonella spp. In Egypt, recurrent Salmonella bacteraemia is a wellrecognized complication of S. haematobium infection. Patients with urinary schistosomiasis presenting with a recurrence of salmonellosis should first be treated for their S. haematobium infection.125,177 In the later stages of obstructive uropathy, hydronephrosis may develop and cause renal parenchymal dysfunction which, added to urinary tract infection, leads to impaired kidney function.178 The ominous relationship between bilateral schistosomal uropathy, bacteriuria with impairment of hydrogen ion excretion, non-functioning kidneys and death has been well described.179 Genital Schistosomiasis and Infertility (S. haematobium, S. mansoni) Egg deposition in the genital tract is known to cause inflammation with easily identifiable, pathognomonic sandy patches lesions. In the female cervix, vagina and vulva sandy patches, tubercles and neovascularization can be identified by

52  Schistosomiasis

715

colposcopic examination (Figure 52.16). Studies in Malawi and Zimbabwe have found up to 75% of women with urinary schistosomiasis to have Schistosoma haematobium ova in the genitals.120,180 Of special concern, women with female genital schistosomiasis (FGS) in rural Zimbabwean or Tanzanian communities were also found to have a three- to four-fold risk of having HIV infection.181,182 A recent population-based study has linked FGS with female infertility and sub-fecundity in endemic communities.122 Although rarely reported, there are cases of transitional genital schistosomiasis with S. mansoni in Brazil.183 Little is known of its impact in later reproductive health. For men, haematospermia is often a presenting symptom of genitourinary schistosomiasis. Orchitis, prostatitis, dyspareunia and oligospermia are associated with male genital schistosomiasis and have been shown to resolve after anti-schistosomal therapy.118,119 Intestinal Schistosomiasis (S. mansoni, S. japonicum, S. intercalatum and S. mekongi) – Common Features The wider spectrum of clinical presentations in schistosomiasis has been highlighted in recent decades through the increased use of community-based surveys as a tool for investigation, in contrast with the classical descriptions of disease among hospitalized patients. The majority of persons infected with S. mansoni or S. japonicum have milder complaints and nonspecific symptoms, in agreement with the known epidemiological and biological distribution of the parasite within the human host. In general, the advanced clinical features of Schistosomarelated pathology are encountered in only a small proportion of patients with long-term infection. Intestinal disease may manifest as chronic or intermittent diarrhoea with blood in the stools, by abdominal discomfort or pain, or by colicky cramps. Severe dysentery is rare but occurs. Among such patients, secondary symptoms of fever, weakness, fatigue, anorexia and weight loss are frequent.184 In epidemiological surveys, there are significant correlations between visible or occult blood in the stools, abdominal pain and diarrhoea.185 S. mansoni can present with acute schistosomiasis, general ‘subtle’ symptoms as explained above, or with hepatomegaly (often of the left lobe) which may be combined with significant splenomegaly. In the later stages of infection, there can occur a chronic catarrhal state of the intestine, with swollen, granular mucosa and loose stools with blood and/or mucus, or an intermittent dysenteric syndrome.186 The anatomic complications of polyposis and hepatosplenic schistosomiasis each have their own symptomatology; polyposis produces what is, in effect, a severe, chronic dysentery with blood and protein loss (Figures 52.18, 52.21). Intussusception and/or rectal prolapse may occur. Hepatosplenic schistosomiasis presents as upper abdominal discomfort, left upper abdominal pain or a swelling of the abdomen (Figure 52.22). Physical signs include a firm enlargement of the liver, often with splenomegaly. The spleen may become greatly enlarged, sometimes extending downwards past the umbilicus into the left iliac fossa and may even at times fill most of the abdomen. Ascites may be present, but the classical signs of hepatocellular disease (cirrhosis), i.e. spider-web angiomata, gynaecomastia, palmar erythema, jaundice and alterations in hair distribution are not present in ‘pure’ schistosomal disease. They may, however, be

716

SECTION 10  Helminthic Infections

A common primary presenting sign of hepatosplenic disease in schistosomiasis is haematemesis from gastrooesophageal varices. This may occur without warning or may be preceded by a feeling of weakness or upper abdominal discomfort; patients have classical signs of acute blood loss with sweating, pallor, thirst, somnolence and a lowered blood and pulse pressure. In many cases, melaena follows and this acute episode may precipitate ascites and/or peripheral oedema. Fatalities may occur with the primary haemorrhage if treatment is not available; recurrent multiple haemorrhagic episodes are usual. Unless complicated by hepatitis B, C, D or E, liver function abnormalities and hepatic encephalopathy do not develop. Where mixed infections of S. mansoni or S. japonicum and the various hepatitis viruses co-exist, the downhill clinical course is correspondingly rapid and the typical signs of hepatocellular failure appear with, in parallel, a poor prognosis.

Figure 52.21  Barium contrast radiograph of colonic polyposis due to intestinal schistosomiasis. (From Peters W, Pasvol G. Atlas of Tropical Medicine and Parasitology. Copyright © 2006, with permission from Elsevier.)

found where hepatitis B, C, D or E co-exist with schistosomal periportal fibrosis and lead to post-hepatitic hepatocellular damage. In a recent study, co-infection with S. mansoni and hepatitis C (HCV) had significant worsening of fibrosis, compared with subjects with HCV infection alone.187 In the most advanced cases of intestinal schistosomiasis, endocrine changes can be found: growth retardation, infantilism, retarded bone age, all probably due to hypopituitarism. Amenorrhoea, early menopause, infertility and loss of libido have been attributed to a similar cause.

Figure 52.22  A 52-year-old man with a grossly enlarged abdomen caused by the portal hypertension of advanced chronic schistosomiasis. (From WHO/TDR/Crump.)

S. japonicum and S. mekongi.  Whereas infections with the oriental schistosomes follow a broadly similar clinical course to that of S. mansoni, several distinct differences are noted. In general, infection with S. mekongi is milder than that with S. japonicum. Hepatosplenomegaly is common, but cerebral and cardiopulmonary complications are not reported with S. mekongi. In the past, there have been more hospital-based clinical studies of S. japonicum than community-based investigations. Hence, the clinical descriptions have been slanted towards advanced cases. In fact, at least half of patients infected with S. japonicum are not severely symptomatic. General symptoms, fatigue, weakness, nonspecific abdominal discomfort and irregular bowel movements or intermittent diarrhoea are frequent. Chronic diarrhoea is said to be a common complaint and lower abdominal pain is a frequent symptom.115 The presence of diarrhoea is of particular importance in children, where it is a strong predictor of chronic progression to advanced disease.188 The later signs of hepatosplenic schistosomiasis evolve as do those of S. mansoni infection. Although schistosomal dwarfism was not uncommon in China in the first half of the twentieth century, it has become a rarity nowadays. Cardiopulmonary and renal complications are well known.189 The main difference clinically is the occurrence of cerebral schistosomiasis in S. japonicum infection. Spinal cord involvement appears less frequently than with S. mansoni, but such generalizations are difficult, if not impossible, to confirm scientifically. In the acute phase of cerebral schistosomiasis, the presenting symptoms and signs are those of a meningoencephalitis, with pyrexia, headache, vomiting, blurred vision and disturbed consciousness. In the established or chronic phase of the infection, several distinct neurological presentations are recognized; most common is epilepsy, which may be generalized but is more frequently Jacksonian in type; signs suggestive of a spaceoccupying lesion or a stroke are also described. The prevalence of epilepsy in infected communities has been estimated at 1–4%, against a baseline rate of 0.3–0.5%.189 With advances in neuroradiology, in the presence of positive serology or parasitology and with or without operational biopsy, modern imaging techniques may prove diagnostic. S. intercalatum.  In comparison with S. haematobium or S. mansoni infection, clinical symptoms of disease are commonly mild in S. intercalatum infection and it has not been regarded

as a major public health problem.190 Active infection is most common among children and adolescents and pathology is most often detected among those with egg excretion in excess of 400 eggs/g of faeces.151 S. intercalatum infection can present with diarrhoea and lower abdominal pain or discomfort, but the classic presentation is that of rectal bleeding that can complicate to develop severe rectitis.190 Conversely, some patients may present only with haematuria. In a report from Nigeria, S. intercalatum eggs were found in the urine but not in faeces in 6% of the 1709 people surveyed.151 It is believed that the natural hybridization between S. intercalatum and S. haematobium can produce an atypical clinical picture with ‘ectopic’ localization of worms.191,192

Differential Diagnosis In an infection of such diverse clinical manifestations it is scarcely surprising that schistosomiasis in any of its forms can be confused with many other disease processes. Acute schistosomiasis (Katayama syndrome) must be differentiated from typhoid fever, brucellosis, malaria, leptospirosis and numerous other causes of pyrexia of uncertain origin (PUO). Pyrexia and eosinophilia occur in trichinosis, tropical eosinophilia, visceral larva migrans and infections with Opisthorchis, Paragonimus and Clonorchis spp. Urinary schistosomiasis due to S. haematobium must be distinguished from other causes of haemoglobinuria, including cancer of the urogenital tract, acute nephritides and other infections, including rare conditions such as renal tuberculosis with haematuria. Abdominal symptoms commonly seen in S. mansoni, may suggest peptic ulcer, biliary disease or pancreatitis; in such cases, if schistosomiasis is the cause, symptoms typically abate after specific anti-schistosomal treatment. Lower abdominal conditions to be excluded are the various forms of dysentery, particularly amoebic dysentery, ulcerative colitis and non-schistosomal polyposis. Hepatosplenomegaly can be due to multiple causes; its possible aetiology is wide and embraces all causes of hepatomegaly and splenomegaly, separately and combined. The marked splenic enlargement of portal hypertension due to periportal fibrosis must be distinguished from kala-azar (visceral leishmaniasis), certain of the chronic leukaemias or myeloproliferative syndromes, some of the haemoglobinopathies (e.g. thalassaemias) and the tropical splenomegaly syndrome. Other Syndromes and Presentations.  Schistosomiasis must always be considered as one of the causes of cor pulmonale and virtually any neurological presentation, but particularly the various forms of epilepsy and the different types of myelopathy or spinal cord compression syndromes. A broad knowledge of local and/or regional epidemiology paired with a high index of diagnostic suspicion will contribute to the avoidance of diagnostic error.

Diagnosis A definitive diagnosis of an active Schistosoma infection is made by the direct visual demonstration of parasite eggs (see Figure 52.3) in bodily excretions or secretions, usually the stool or urine or alternatively in material from rectal biopsy or biopsies

52  Schistosomiasis

717

from liver (see Figure 52.19) or surgically removed tissue. A sensitive direct diagnosis can also be made by hatching tests in which swimming miracidia originating from excreted eggs can be seen with the naked eye. This is an indication beyond doubt that the eggs are viable and have originated from living fertilized female schistosomes. A recent addition to direct diagnostic techniques is the detection of schistosome antigens in serum or urine: circulating anodic antigen (CAA) and circulating cathodic antigen (CCA). These two glycoprotein circulating antigens associated with the gut of the adult worm are well characterized, are genus specific and their presence indicates active human infection by S. mansoni, S. haematobium, S. japonicum, or S. intercalatum. They are detected by immunoassay and have virtually 100% specificity and very high sensitivity. Patently, they offer new possibilities for epidemiological and post-chemotherapeutic monitoring. Commercial point-of-care assays for detection of CCA in the urine have been developed and are undergoing field trials for their performance characteristics in population-based control programmes. DIRECT DIAGNOSTIC TECHNIQUES Parasitological Diagnosis No single diagnostic technique is optimal for all situations. Most of the currently used parasitological techniques can be interpreted qualitatively or quantitatively depending on a programme’s diagnostic needs. Quantitative techniques are most often used in research studies, in experimental chemotherapy and clinical trials, in epidemiological surveys, or in the evaluation of allied intervention measures for transmission control. In an individual clinical setting, it is customary to examine repeated specimens of excreta parasitologically (in practice, three specimens) before declaring a patient to be ‘egg negative’ and most likely not chronically infected by Schistosoma spp. Because eggs must migrate through host tissue to reach the stool or the urine, egg shedding can persist for some time after active infection is cleared. Confirmation of a diagnosis by hatching tests demonstrates that the eggs are viable and an active infection exists; the finding of only dead eggs in the excreta is not an indication for further anti-parasite treatment. Egg Counting The direct demonstration of eggs has an advantage over all other diagnostic measures because specificity is obviously maximal, yet an unquestioning belief in the absolute merits of quantitative diagnosis is not justified. Egg counts are indirect estimates of worm loads; they vary in time and place and between technicians and an assumed Poisson distribution of eggs in the excreta may not be valid.193 Standard tests routinely misdiagnose as ‘uninfected’ those individuals who carry light infections.194 Standard methods such as the Kato-Katz stool test for intestinal schistosomiasis are only 40–60% sensitive when performed on a single stool specimen.8,10 This becomes relevant in adequately assessing the true burden of Schistosoma infection and infection-associated disease both on an individual level and within an affected community. Misclassification bias (due to this routine underdiagnosis) effectively limits our appreciation of the overall health impact of this very common human parasitic infection.12

718

SECTION 10  Helminthic Infections

Diagnosis of S. haematobium Infection Ova of S. haematobium are most easily detected in the urine. A qualitative diagnosis can be made by the microscopic examination of a sedimented or centrifuged urine specimen of known volume. Filtration techniques, which yield a quantitative estimation of egg excretion, have mostly replaced simple sedimentation and/or centrifugation and are the norm in epidemiological studies. The preferred field test is by using the Nuclepore polycarbonate filters.195 There are other less preferred methods using other types of polycarbonate or polyamide filters.195–197 The principle common to all is that eggs are retained on the filter and can be counted with or without staining. Many different stains are in use and preferences are largely personal; eggs may be ‘stored’ in preservative or a preservative-stain mixture. As with all techniques, problems arise during field usage. Falsenegative epidemiological results may occur from loss of eggs during bulk transport of dried filter papers,197 and in a small but significant proportion, eggs can be retained on polyamide filters (Nytrel) even after careful attempts to wash and reuse them. As a general rule, any filter should be used once only and then discarded. Diagnosis of Intestinal Schistosomes In infections with S. mansoni, S. japonicum, S. mekongi and S. intercalatum, where eggs are excreted in the faeces, simple comminution of the stool and sedimentation before microscopy is a reliable diagnostic technique. Direct saline microscopy of stool has a very low diagnostic sensitivity owing to the small amount of the faecal sample examined. Many concentration techniques have been described.198–201 All involve removal of fat, faecal debris and mucus and of necessity require more sophisticated laboratory facilities. They find their optimal use in the detection of ‘light’ infections where egg excretion is of a low intensity or is intermittent. Presently, the cellophane thick faecal smear (the Kato technique or one of its numerous modifications) is the standard diagnostic tool202,203 in most clinical and epidemiological studies. Essentially a semi-concentration-clearing-staining process, it is a simple microscopic method examining 20–50  mg of stool, depending on the template used and is quantitative, thus permitting the comparisons of data from site to site. It can be performed in the field and may be used at the primary healthcare level. The prepared slide takes some time to clear; this varies with ambient temperature and humidity. Slides can be stored for at least 1 week, often longer, the time again being variable, so that assessments of technicians’ counts can be incorporated into a system of quality control. An advantage lies in its use in the diagnosis and counting of eggs of many intestinal nematodes or cestodes (e.g. Ascaris lumbricoides, Trichuris trichiura, Taenia spp. and hookworms), although to assess hookworm egg excretion, counts must be made within 15–30 min after slide preparation because hookworm eggs disappear after this period owing to breakdown and hatching within the Kato solution. The exact details of the procedure must be calibrated for each working location, taking into account environmental variables, resources and locally available material and human resources. Disadvantages of the standard Kato-Katz technique are that watery or diarrhoeal stools cannot be processed and dietary habits may result in hard fibrous stools that are difficult to process. Additionally, there is a definite lower limit of 24–

50 eggs/g of stool detectable on a single smear, with only 40– 60% sensitivity for detecting active infection in a single day’s stool specimen.10 For this reason, it is common practice to examine two or three subsamples of each individual faecal specimen and to perform repeated daily exams (≥3) to more reliably detect infection. Whichever technique is used, it is vital that the amount of stool examined, whether in a single examination or by a number of subsample examinations, should be reported, so that valid comparisons can be made between areas. A variant of the thick smear technique for S. mansoni infections is the glass sandwich technique204,205 which has been used widely in the Sudan and Malawi. The technique requires no reagents and it has been suggested that it is more cost-effective than other similar quantitative methods. A small-scale experiment showed no significant differences in egg recovery or in methods, readers or slides prepared from the same stool specimens and processed by either the Kato or glass sandwich technique.206 Further comparisons on a larger scale are needed and a major disadvantage of this technique is that it is limited to use in restricted endemic areas; hence comparison of findings with other endemic areas is, at present, invalid. Eggs of S. mansoni or S. intercalatum are often found in the urine. In one series, 15% of patients with a sole S. mansoni infection had ‘mansonuria’, but this is an unusually high rate.207 Miracidial Hatching Described originally by Fulleborn in 1921208 and in routine use in biological and chemotherapeutic studies for decades, hatching is generally accepted as the most sensitive of all parasitological methods in all forms of schistosomiasis. The method remains essential for adequate post-treatment evaluation in clinical trials. However, its use in field studies has been less common because standardization and quantification are more difficult than for techniques where eggs can simply be counted. Diagnosis and follow-up of treated patients in the huge Chinese control programmes of the 1960s and 1970s were based on a ‘nylon network running water sedimentation technique’, essentially a field-adapted miracidial hatching process.209,210 The relative ease of isolation of eggs from urine has led to many more attempts to quantify hatching procedures in S. haematobium than in S. mansoni infections. As a rough estimate of the numbers of hatchable eggs, the miradiascope was used as a macroscopic technique routinely for surveys in southern Africa.211 More sensitive and accurate hatching techniques have followed212 and further refinements are appearing;213–215 undoubtedly the use of ‘wet’ preparations has complicated field standardization, but hatching retains its primacy as the most sensitive diagnostic tool for S. haematobium infection. In S. mansoni infections, many variants of hatching techniques exist, some semi-quantitative and all possessing high sensitivity.216,217 In S. japonicum-endemic areas in China, miracidial hatching is widely and routinely used for both epidemiological surveys and as an indicator of parasitological cure after chemotherapy.136 Rectal Biopsy Used for decades as a simple direct diagnostic technique at the individual clinical level, rectal biopsy may be employed in addition to faecal examination and provides an effective way of

visualizing eggs. Small biopsy specimens of mucosa are soaked in water and examined microscopically as a crush preparation. In the intestinal dwelling species, egg viability can often be determined by observation of flame cell or miracidial movement within the eggshell. Biopsies may be taken from rectal valves via a crocodile forceps or with a curette and proctoscope, a much simpler procedure; the mucosa is pulled over the end of the proctoscope and cut off with the curette.218 Ova of S. haematobium in rectal snips are typically non-viable and will appear black. In Brazil, the oogram technique (a quantitative rectal biopsy with division of eggs into developmental stages) is commonly used in assessment of the effects of anti-schistosomal drugs.218 Other Biopsy Sites As expected, schistosome ova are frequently found in other biopsy locations, such as the liver, bladder, cervix, vagina, perineum and skin and indications for a biopsy of such sites lie at the individual clinical level. Indirect Diagnostic Techniques Given a high index of suspicion based on exposure history or local epidemiology, the diagnosis of active Schistosoma infection or persistent schistosomiasis can be based on physical or radiological signs, seroimmunological assessment, or in the case of S. haematobium infection, the detection of red blood cells in the urine. Chemical Reagent Strips Indirect diagnostic techniques are used most frequently for S. haematobium infections. The application of chemical reagent strips (CRSs) that are used to detect haematuria and/or proteinuria in a semi-quantitative fashion219 is used as a diagnostic surrogate in endemic areas; a positive result is interpreted as indicating active infection. False-positive reactions occur in myoglobinuria and in the presence of bacterial peroxidases resulting from heavy bacteruria, while inhibition of the reactions may occur if urinary ascorbic acid levels exceed 10 mg/100 mL urine. False positives for proteinuria occur in alkaline urines or when quinine or a quinine derivative is present. False negatives have occurred in strongly acid urine with Bence Jones proteinuria and in urine containing predominantly γ-globulin. In areas endemic for S. haematobium, there is good correlation between reagent strip reactions indicating haematuria and/or proteinuria and increasing intensity of egg output.9,220,221 Good predictive values resulting from high sensitivity and the relative specificity of CRSs in S. haematobium-endemic areas emphasize the limitations of conventional single-urine microscopic examinations at very low egg output levels and confirm the validity of CRSs in detecting those with a ‘high’ egg output (i.e. over 50 eggs/10  mL urine)9 CRSs can be used in areas of both high and low transmission and typically find their optimal use in the detection of those with heavy infection. Immunodiagnosis Serodiagnostic techniques are used for the detection of either specific antibodies or genus-specific antigens. Antibodies to adult worm, schistosomular, cercarial or egg antigens can be detected by a number of different procedures, including the

52  Schistosomiasis

719

various forms of enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), indirect immunofluorescence tests (IFAT), gel precipitation techniques (GPT), indirect haemagglutination (IHA), latex agglutination (LAT) and circumoval precipitin tests (COPT) which have superseded the older Cercarien-Hüllen reactions (CHR) and complement fixation tests (CFT). In general, antibody detection techniques have been less useful to the practicing physician and epidemiologist than the techniques of direct parasitological diagnosis. Their basic disadvantage is that they all point to past exposure to mammalian or, in rare instances, avian schistosomes without indicating the duration, activity, or quantum of infection. Further disadvantages are an absence of globally agreed criteria of performance and standards; the necessity for expensive equipment, costly or labile reagents; the need for skilled technical personnel; and the slow diminution of specific antibody level after treatment, thus reducing their value as a marker of chemotherapeutic success. Each laboratory in endemic or non-endemic areas has tended to use its own particular antigen and assay procedure. The WHO has conducted several collaborative studies222–224 in attempts to improve the technology and to standardize both antigens and procedures. A recent field study conducted in schoolchildren in Zanzibar to evaluate the performance of the SEA-ELISA using sera from finger-prick blood was good; a sensitivity of 89% and specificity of 70%, showing promise for the SEA-ELISA as a complementary field-test.225 Immunodiagnostics are also useful in acute schistosomiasis, where sensitivity of antibody testing for Katayama syndrome is estimated to be approximately 70–80%. A 4-year investigation of confirmed acute schistosomiasis cases among travellers reported a positive antibody diagnosis in 15 out of 23 (65%) of patients at first presentation, compared with ova detection in only five out of 23 (22%) patients.114,158 Advances have also been made in antigen detection tests.13,225,226 Improvements in the production of monoclonal antibodies have led to new diagnostic tests of CAA and CCA in serum and urine. In a recent study conducted in Uganda and Zanzibar, the sensitivity and specificity of the CCA dipstick was 83% and 81% for detection of Schistosoma mansoni, respectively. By contrast, the antigen dipsticks failed to reliably detect S. haematobium-infected children, even in the presence of eggs in urine, a phenomenon perhaps related to the presence of interfering inflammatory substances in the urine. This finding limits the diagnostic use of urine-based antigen detection to S. mansoni-endemic areas for now.110 Radiology Various imaging procedures for detecting morbidity from schistosomal infection (Figures 52.15, 52.21, 52.23) have long been in use as a form of indirect diagnosis in hospital practice. These include ultrasonography, plain abdominal radiography to detect calcification, intravenous pyelography to detect bladder and ureteral changes or obstructive uropathy, isotope renography, computed tomography for cerebral schistosomiasis, myelography for suspected cord damage and portal venography for hepatosplenic schistosomiasis with portal venous hypertensive changes. Complications, such as gastrointestinal bleeding may require the use of specialized techniques, such as splenoportography or nuclear isotopic studies of hepatic blood flow. The indications for a particular investigation lie at the individual patient level and test selection should be

720

SECTION 10  Helminthic Infections

based on consultation between the treating physician and the radiologist. Ultrasonography With the introduction and expanded use of ultrasonography there have been major changes in the diagnosis of Schistosomaassociated morbidity, both at the individual patient level and at the community level. The technique is non-invasive, simple, portable, has no biological hazard to the patient or the operator and either complements or is an alternative diagnostic method to many older invasive techniques. With the exception of hydroureter, ureteral calculi and bladder calcification, it has, in comparison with other diagnostic procedures, high specificity and sensitivity, is superior to physical examination in measuring liver and spleen size and is the best technique for grading schistosomal periportal fibrosis, portal hypertension, hydronephrosis, urinary bladder wall lesions and renal and bladder stones.227 WHO has published consensus guidelines for ultrasound examination in abdominal and genitourinary schistosomiasis (Figure 52.23), and an extensive review of technical and clinical experience is available.228,229

Management and Treatment The primary objective of treatment is cure of the individual patient by eradication of the Schistosoma infection from which the patient suffers. Cure leads to cessation of egg deposition (the pathogenic mediator in host tissues) and this prevents additional organ damage; existing lesions will, in the vast majority of cases, improve or regress. Since the 1960s, there have been major advances in chemotherapy for the treatment of schistosomiasis. The introduction and widespread use of the current highly effective, orally administered, well-tolerated anti-schistosomal drugs have provided physicians, epidemiologists and public health practitioners with therapeutic opportunities not available in the first half of the twentieth century. For mass drug administration programmes (now the standard in large-scale, community-based chemotherapy), the main aim is to reduce the average burden of Schistosoma-associated morbidity by the greatest amount possible. Individual ‘cure’ may or may not occur. However, in some endemic settings, the community may benefit as a whole by an important ‘externality’ of mass treatment – the blocking of the egg–miracidium–snail stage of the parasite life cycle, which reduces transmission by minimizing pollution of water supplies and thus diminishes cercarial exposure at human water contact sites.68,230,231 Praziquantel Praziquantel is the drug of choice for schistosomiasis and is effective against all Schistosoma species that occur in humans. It is also effective in the other snail-borne trematode infections – clonorchiasis, paragonimiasis and opisthorchiasis – and in infections due to the adult cestodes, Taenia solium, T. saginata, Hymenolepis nana and Diphyllobothrium spp. Although dosage is standardized in large-scale morbidity control programmes,23 there may be variation in dose in the treatment of the individual patient.232 In field programmes, a single oral dose of 40  mg/kg is effective in S. haematobium, S. mansoni and S. intercalatum infections. For S. japonicum infection, the dose recommended is a total of 60  mg/kg, given at 4-hourly intervals as three 20  mg/kg doses or two

A

A. Normal

B. “Starry sky”

C. “Rings and pipe-stems”

D. “Ruff” around portal bifurcation

E. “Patches”

F. “Bird’s claw”

2.0 cm 1.5 cm 1.0 cm 0.5 cm 0.0 cm Wait

Irregularity

Thickening

Mass

Pseudopolyp

B

1.0 cm

C

Score = 0

Score = 6

Score = 8

Figure 52.23  Schematic of abnormal ultrasound findings for schistosomiasis. (A) Images showing abnormal liver parenchymal patterns associated with schistosomiasis mansoni; (B) Classification of schistosomiasis haematobia-related bladder lesions. (C) Measurement of the congestive dilatation of the renal pelvis in urogenital schistosomiasis. (From Richter J, Hatz C, Campagne G, et al. Ultrasound in schistosomiasis: A practical guide to the standardized use of ultrasonography for the assessment of schistosomiasis-related morbidity. Geneva: World Health Organization; 2000. Report No.: TDR/STR/SCH/00.1.)

30  mg/kg doses.233 However, in some regional control programmes, current practice is to treat S. japonicum with a single oral dose of 40 mg/kg. The usual total dose for S. mekongi is 60  mg/kg, although there is evidence that repeated treatment at this dosage may be necessary for cure of this species.233,234 For treatment of individual patients with heavy infections with S. mansoni (over 800 eggs/g of stool), a total dose of 50 or 60 mg/kg, given in two equally divided doses 4–6 h apart, may be needed; single doses are best given after food and, if possible, in the evening. Patient tolerance is extremely good and virtually all trials have confirmed the absence of toxicity in the liver, kidney, haematopoietic system, or other body organs and functions.

However, minor side-effects do occur; those related to the gastrointestinal tract are epigastric or generalized abdominal pain or discomfort, nausea, vomiting, anorexia or loose stools. These side-effects are generally mild, transient and rarely require medication. A rare event in patients heavily infected with S. mansoni or S. japonicum is the passage of blood in the stools after praziquantel treatment. The explanation is unknown; it occurs a few hours after dosage but recovery is rapid and without clinical sequelae. Headache and dizziness may be encountered, as may fever, pruritus or a transient skin eruption, none of which is serious or lasting. Side-effects that occur in field treatments tend to be more frequent in foci of intense transmission and should not be used as an argument for reduction of the dose. ‘Cure rates’ for praziquantel therapy are high; it can be expected that the rate of ‘egg-positive’ to ‘egg-negative’ conversion will be around 80% in research studies. In large-scale field operations, where supervision is less stringent and where compliance with assigned treatment may be difficult to ensure, cure rates of 50–60% are typical when a single oral dose of 40 mg/kg is scheduled to be dispensed; egg output reduction in those treated but not ‘cured’ should exceed 90% of pre-treatment output.230,235 Questions are frequently raised about the emergence of parasite resistance to praziquantel. Cure rates after praziquantel treatment in a new highly endemic focus of intense transmission of S. mansoni in northern Senegal in the early 1990s were alarmingly low.236 A further increase in praziquantel dose did not improve the outcome.237 However, a WHO consultation decided that the intensity of transmission in this focus was such as to cause the initially observed low cure rates, because praziquantel is ineffective or at least less effective against maturing worms.238 In such a new focus, among non-immunes, experiencing a high intensity of transmission, immature worms would be present in the majority of patients. Once these ‘refractory’ patients were removed from any exposure to reinfection, their Schistosoma infections rapidly responded to standard praziquantel therapy.239 There is good evidence from the Nile Delta that some 2–3% of patients still excrete eggs after two or three rounds of praziquantel treatment. In this setting, some 20% of field isolates transferred in to experimental mouse models of infection showed a normal susceptibility to praziquantel, but some of the remaining isolates required two to six times the normal dose to achieve a 50% reduction in worm numbers in laboratory testing. However, this reduced susceptibility was not increased upon repeated passages under drug pressure. Thus, evidence exists that certain schistosome isolates or strains of the parasite are inherently less susceptible to praziquantel. In Egypt, follow-up in areas where praziquantel has been used intensively indicates that the widespread use of the drug has not resulted in a dramatic change in its curative efficacy.240 Although this ‘resistance/tolerance’ phenomenon has been reported in human S. mansoni, no evidence exists at present of ‘resistance’ in S. japonicum or S. haematobium infections. In the latter case, theoretical mathematical modelling suggests that the emergence of resistance might take some 7 years on an annual treatment coverage of 100% of an infected population. As this coverage is rarely, if ever, obtained in field practice, where a range of 25–75% compliance is more usual, emergence of resistance may take more than 20 years.241 Review of praziquantel treatment given in pregnancy has not shown evidence of detrimental effects to the mother or the

52  Schistosomiasis

721

fetus. This post-release experience, combined with available animal safety data has led to a WHO recommendation in favour of using praziquantel for treatment of Schistosoma-infected pregnant or lactating women after the first trimester of pregnancy.242 A subsequent randomized, placebo-controlled trial of deworming in pregnancy has confirmed the safety of praziquantel therapy in infected pregnant women.243 Oxamniquine A tetrahydroquinolone compound distantly related to hycanthone, oxamniquine is effective only against S. mansoni. Oxamniquine is used at all stages, from acute toxaemic to chronic and complicated S. mansoni infections, with good results. In animal studies, one peculiarity noted about the drug was that male worms proved more susceptible than female worms. Egg-laying by surviving females ceased in the absence of males after successful treatment, thus removing the basic pathogenic mechanism in Schistosomiasis mansoni.244,245 Oxamniquine is available as capsules of 250 mg or as a syrup containing 50  mg/mL and is marketed as Mansil® in South America and as Vansil® in Africa. It is listed in the most recent WHO Model of Essential Medicines as a ‘complementary drug’ for use when praziquantel treatment fails.246 Advanced S. mansoni infection with hepatosplenomegaly, portal hypertension and/or ascites responds well and in schistosomal polyposis there are great improvements in both the associated anaemia and protein-losing enteropathy.247–249 High cure rates (60–90% in different studies) are seen after oxamniquine treatment of uncomplicated S. mansoni infection. From 1975 to 1979, oxamniquine was used in a major control campaign in Brazil, when some 5 million doses were given in the field programmes with high cure rates and very good tolerance.250 The dose of oxamniquine varies with the geographical origin of the S. mansoni infection, the age and hence the surface area of the patient. In South America, adults are given 15 mg/kg of body weight as a single oral dose; in children 20 mg/kg is preferred, given in two divided portions each of 10 mg/kg with an interval of 4–6 h between doses. If practicable, the drug should be given after food or just before sleep. With the S. mansoni that is found on the African continent, only those with strains of West African origin are given the same doses as in South America. In Egypt, Sudan and southern Africa, a total dose of 60 mg/kg body weight is used, either as 15  mg/kg for 2 days or as 20  mg/kg once daily for 3 days. In East Africa, a total dose of 30–40  mg/kg is given in a split regimen over 1 or 2 days. In general, oxamniquine is well tolerated. There are virtually no contraindications but classes of patients exist who require close monitoring: Patients with a history of any form of epilepsy must be supervised for 48  h after treatment because a small number of epileptiform convulsions have been reported, as have generalized seizures after the drug, fortunately without sequelae and with clinical and electroencephalographic recovery.251,252 Studies are lacking regarding safety of oxamniquine in pregnancy, so as a precaution, it should not be given during the first 4 months of pregnancy. Any patient whose occupation involves care of heavy machinery or who is employed in the transport industry (e.g. pilots, truckers, dockers, crane drivers) should be placed off work for 48 h after treatment.

722

SECTION 10  Helminthic Infections

Side-effects are uncommon; dizziness, drowsiness and headache are most frequent but last for some 4–6 h only. Hallucinations and a state of excitement are very rare events. Although abdominal discomfort, vomiting and diarrhoea do occur, there is no constant statistical correlation and, in practice, adverse effects have had no influence on compliance in field programmes. A harmless orange–red discolouration of the urine may occur but is transitory and a syndrome of peripheral blood eosinophilia, peaking at 7–10 days, scattered pulmonary infiltrates and increased immune complexes in serum with urinary excretion of schistosomal antigens is known in Egypt but has not been described in other locations. In summary, oxamniquine is a highly useful drug for treatment of all forms of S. mansoni infection, including many advanced and complicated syndromes. DRUG RESISTANCE No new anti-schistosomal drugs can be expected to emerge in the international scene in the near future, as a consequence of there being little or no pharmaceutical industry profit (with slim prospects of developmental cost recovery) from antihelmintic sales within Schistosoma-endemic countries. Thus, praziquantel remains the only practical treatment option for anti-schistosomal campaigns in the present day. As a result, the importance of monitoring for true praziquantel drug resistance cannot be overemphasized, although at present there are few such efforts. Evidence for Schistosoma mansoni resistance to praziquantel has been sought in parasites taken from treated but uncured human patients and in laboratory isolates of S. mansoni subjected to successive passages under drug pressure.253 In community-based treatment programmes, is has been found that higher than usual doses of PZQ have been needed to effectively suppress infection levels in some areas of Egypt and Senegal254 but the levels of drug ‘tolerance’ found among clinical isolates of the parasite so far are low.253 One major problem is the precise quantitative interpretation of cure rates – without a ‘gold standard’ diagnostic for actual worm infection, we currently cannot make an unequivocal distinction between drug failure and the ‘typical’ drug performance in the presence of heavy infectious worm burden, where persistent, low-level infection is the norm after a single round of praziquantel therapy.254 The recent introduction of a simple new technique for assessing the effects of praziquantel on miracidia hatched from eggs may, if confirmed in different species, offer an affordable surveillance device to predict praziquantel ‘resistance’ or ‘tolerance’ in the clinical realm.255 Undoubtedly, this in an area in need of well-designed, long-term longitudinal monitoring programmes. Resistance to oxamniquine is known in South America but is not yet a public health problem, as such patients are treated successfully with praziquantel.256 FUTURE CHEMOTHERAPY Artemisinin Derivatives (Artemether, Artesunate) In the past decade, research in China and West Africa has focused on the potential use of artemisinin derivatives as antischistosomal drugs. These studies all show great promise for

this group of compounds, which were initially developed as anti-malarial drugs.257–260 Artemisinin, first isolated in the 1970s, is the active ingredient of the herb Artemisia annua and is a sesquiterpene lactone containing a peroxide bridge. Several semi-synthetic derivatives including artemether and artesunate have been generated. These are among the most potent antimalarials currently available. It has been shown that artemisinin derivatives can most effectively kill immature worms (schistosomula) during the migratory period 2–5 weeks after infection, a time when worms are relatively insensitive to praziquantel. As such, the artemesinins can have therapeutic effects against acute infection (with associated preventive effects against establishment of chronic infection) in Schistosoma infections. Such effects are seen both in animal models and indirectly, in human clinical trials.261 Another randomized placebo-control trial, in an area of Cote d’Ivoire endemic for S. mansoni, found that oral artemether treatment resulted in lower incidence of S. mansoni and lower egg outputs among infected subjects, when compared with a placebo-treated group.260 However, because artemisinin derivatives are one of the mainstays of current antimalarial chemotherapy and because endemic malaria and endemic schistosomiasis co-exist in numerous areas, especially in Africa, wider use of these derivatives must await the clarification of their joint distribution, along with questions on the potential introduction of drug resistance among Plasmodium spp. through wider use of artemether drugs as ‘monotherapy’ for schistosomiasis without full coverage for malaria (artemisinin-combination therapy is the established norm for malaria therapy). Assessment of Chemotherapy Outcomes Assessment of patients treated for schistosomiasis is conducted by repeated clinical observation, evaluation of symptom improvement and diminution or disappearance of physical, radiological, particularly ultrasonographic or endoscopic signs of disease. Direct parasitological examination of urine, stool or rectal biopsy is essential and should be performed on repeated (three) specimens of excreta at about 6–8 weeks and 4–6 months after treatment by selection of appropriate parasitological techniques detailed above. Follow-up is simple if no reinfection risk is present; however, in endemic areas where transmission persists, the explanation of viable eggs in the excreta 4–6 months after therapy is less clear. Such post-treatment egg excretion may be due to a maturing prepatent infection that was unaffected by praziquantel chemotherapy, to a true reinfection or to a therapeutic failure. It is not always easy to decide which event, or even combination of events, is responsible. Increased use of antigen detection techniques (e.g. CAA, CCA) offers possibilities for detection of persistent low-level adult worm infection, which may provide clarification of these issues. SPECIAL CLINICAL SYNDROMES AND MANAGEMENT Neurological Schistosomiasis The efficacy and safety of modern anti-schistosomal drugs has led to early treatment of encephalopathies, myelopathies or

other spinal cord syndromes that are reasonably suspected (even if not proven) to be due to schistosomiasis. This improves prognosis, as risk of cord damage in myelopathy is closely related to delays in diagnosis and the time taken to provide effective therapy. Cerebral schistosomiasis has better prognosis than spinal schistosomiasis. The presence of antibody responses to schistosomal antigens262 or the presence of circulating parasite antigens (CCA, CAA) can be diagnostic in cases of acute schistosomiasis or light-intensity infections where eggs are not reliably excreted. These two diagnostic techniques should be used when available; unfortunately they are, as yet, restricted only to certain hightechnology referral laboratories. The use of corticosteroids in neuroschistosomiasis remains controversial but in clinical settings they are commonly used.263 Laminectomy is an important intervention in acute paraplegia with spinal cord compression or block. In S. japonicum, suspected cerebral schistosomiasis should be localized with modern imaging techniques (CT, MRI) and treated with praziquantel, which has proven safe and effective. Computed tomography demonstrates resolution of intracerebral masses, regression of cerebral oedema and the subsequent disappearance of epilepsy.264 Appropriate neurosurgical intervention should be available in case of deterioration due to increasing intracranial pressure or hydrocephalus. An enzyme-linked immunoassay test in cerebrospinal fluid for the diagnosis of neuroschistosomiasis has showed promising results, but needs further validation.265 Acute Toxaemic Schistosomiasis (Katayama Syndrome) There is great controversy on the use of steroids, based primarily on anecdotal evidence; some case reports favour their use266 but others do not, as clinical deterioration can follow after commencement of treatment.267 As a general principle, Katayama syndrome patients should be treated with praziquantel, which is effective against all Schistosoma species.114,158 The use of artemethers in this setting remains an area of active clinical investigation. Associated Salmonellosis Chronic or recurrent bacteraemia due to Salmonella typhi or S. paratyphi can be due to the presence of concurrent chronic Schistosoma infection. This is due to the colonization of the integument or the gut of the adult schistosome by these bacteria. Although clinical response to antibiotics is good, bacteraemia will recur unless the underlying schistosomiasis is also treated. In this setting, the therapeutic response to antischistosomal drugs is good. Associated Hepatitis Even if, in hepatosplenic schistosomiasis, there is serological or other evidence of an associated hepatitis B infection (or C, D or E) and activity of schistosomiasis is still present, it is worthwhile treating the latter with praziquantel. This is because active schistosomiasis may enhance inflammatory response to chronic hepatitis virus infections in the liver and hasten the onset of cirrhosis. Cirrhosis is not part of Schistosoma-related liver disease, but such co-infection may substantially hasten liver decompensation and the patient’s clinical deterioration.

52  Schistosomiasis

723

Portal Hypertension Chemotherapy is but one part of patient care, as complications are mainly due to the mechanical obstructive pathology resulting from periportal fibrosis. Chemotherapy will not reverse established fibrosis and so treatment at this stage is focused on means to limit portal hypertension and prevent or control any associated variceal bleeding. Whenever Schistosoma eggs are still found in the excreta of such patients, treatment with praziquantel or oxamniquine is indicated and has the usual anthelmintic efficacy in reducing Schistosoma infectious burden. Gastrointestinal Bleeding Admission to a specialized centre is essential (albeit often difficult) in rural endemic areas, because that is where skills in assessment, immediate resuscitation, fibreoptic endoscopy, balloon tamponade and/or endoscopic sclerotherapy are present. The treatment of this complication is beyond the scope of the general physician and is preferably a matter for specialists in this area of intensive care. Emergency portocaval shunts have fallen into disrepute, as a high proportion of operative deaths may occur and, in the survivors, there is frequently a loss of shunt patency and/or development of an associated hepatic encephalopathy. A selective distal splenorenal shunt has been claimed to offer a lower haemorrhage recurrence rate and an improved survival rate.268 The clinical application of β-adrenergic blockade using nonselective β-blockers (e.g. propranolol) for the prevention of an initial gastrointestinal haemorrhage in non-schistosomal cirrhosis, has been proven beneficial.269 However, their use for portal hypertension due to schistosomal periportal fibrosis is controversial: A randomized control trial was forced to have an early termination due to reported adverse events.270 ‘Schistosomiasis Without Eggs’ This term describes cases where no ova can be found on standard parasitological testing but there exists a high clinical suspicion of schistosomal infection, usually based upon an epidemiological history of exposure, the presence of confirmed cases among fellow members of a group, an unexplained eosinophilia after travel to an endemic area and/or a suggestive or suspicious immunodiagnostic test result. In areas endemic for S. haematobium, the presence of a positive test for microhaematuria on urine examination is taken as indicative of infection. Again, the simplicity of use of modern drugs has often clarified difficult diagnostic cases through a ‘therapeutic trial’ of presumptive therapy with praziquantel. Frequently, such treatment is undertaken on suspicion alone, a practice justifiable only when exhaustive efforts to reach a firm parasitological or serological diagnosis have been unsuccessful.

Prevention RISK OF REINFECTION Success of regional control strategies will depend, in part, on what influence local environmental and behavioural factors have on individual risk for primary infection and/or reinfection. Therefore, long-term follow-up studies post-treatment are needed to determine the true benefits of regular ‘preventive chemotherapy’ during a lifetime spent in Schistosoma-endemic

724

SECTION 10  Helminthic Infections

areas.230 In a 9-year follow-up study in Kenya, S. haematobium reinfection risks were associated with location of residence, age less than 12 years, pre-treatment haematuria and frequency of treatment, but interestingly, not cumulative duration of water exposure.68 Reinfection, although initially of light intensity, is not trivial. In the Philippines (in areas endemic for S. japonicum) follow-up studies up to 18 months post-treatment found significant associations between reinfection and increased risk for anaemia of inflammation for all infection intensities.173 Of note, risk for reinfection appears to change over a lifetime, both as a consequence of past parasite exposures and as an effect of changing physiology related to ageing – studies in the Philippines have convincingly found endocrine-related pubertal and postpubertal protection against infection and reinfection with S. japonicum.271 Development of fully effective prevention and control strategies for schistosomiasis will require a thorough understanding of the epidemiology and ecology of transmission, including the presence of suitable environmental factors favouring transmission in relation to patterns of human physiology, exposure behaviour and related social and economic determinants. Control Strategies Whereas current schistosomiasis control measures have focused on ‘morbidity control’ through periodic suppression of infection intensity, new interest has developed in the area of ‘transmission control’, with implied potential for local elimination of transmission with its attendant benefits for untreated individuals. The basic principles for prevention and control are: 1. The reduction in the number of excreted eggs reaching waters harbouring the intermediate snail host(s); this is dependent on health education, the provision and use of adequate sanitary facilities and specific anti-schistosomal chemotherapy for infected communities and individuals 2. The reduction in the probability of miracidial/snail contact; this relies on all factors in (1) above, appropriate modification of the aquatic environment and reduction of intermediate snail host numbers by application of chemical molluscicides or the use of suitable biological control means (e.g. crayfish introduction)272 3. The reduction of cercarial densities, which will occur as a result of all of the preceding actions but overwhelmingly from the employment of molluscicides 4. The reduction of the probability of cercariae locating a definitive host, again due to the cumulative effects of all of the preceding factors plus the reduction of human water contact with infected water bodies by the provision of adequate, safe domestic or peri-domestic water supplies and the substitution of safe recreational water sites273 5. The reduction of the longevity of the adult worms in the human host, a function of chemotherapy 6. The reduction of joint water exposure with reservoir animals, such as water buffaloes, in the case of S. japonicum. Multiple overlaps are obvious in these processes and, conventionally, the stress in ‘prevention’ initiatives is directed towards health education, behaviour modification, the provision of adequate water supplies and sanitation, as supplemented by environmental improvements. ‘Control’ is dominated by chemotherapy and molluscicides, yet lessons learned from China29

and elsewhere273 suggest that integration of these interventions is essential for success and that each endemic focus or region may require an individually tailored clinico-epidemiological, zoogeographical, sociological and environmental approach based on the common principles listed above. Schistosomiasis and 16 other disabling conditions, including soil-transmitted helminths, lymphatic filariasis, onchocerciasis and trachoma have been placed under the broad umbrella of ‘neglected tropical diseases’, brought to public attention through the newly established Global Network for Neglected Tropical Diseases and by new initiatives by the WHO.274 The ultimate aim is to integrate population-based efforts in controlling these diseases in less-developed areas. Effective and efficient integration of NTD control has been shown in state-level regional programmes in Nigeria and Zanzibar and these successes point the way towards implementation in other multi-NTD-endemic areas.275 Based on experience over the past decade, the rationale for the current use of ‘vertical’ de-worming programmes has been reinforced.13,276,277 The Schistosomiasis Control Initiative (SCI), which started its work in 2002, has made substantial progress towards the reduction of Schistosoma-infection-related disease burden in seven partner nations in sub-Saharan Africa.278 Another example of successful treatment-based control is an 8-year programme in Cambodia, where S. mekongi was treated with praziquantel followed with mebendazole for soiltransmitted helminths. The remarkable success of the programme was attributed to strong political commitment despite local limitations in resources.279 Reinfection after chemotherapy remains an ever-present risk in the context of unchanging environmental and socioeconomic conditions. This is because of practical constraints in achieving total population drug coverage and the less than complete cure rates after praziquantel therapy. This means that egg deposition continues locally and therefore transmission continues. Add this to the known hurdles in obtaining environmental modification, provision of sanitation and safe water supplies and the need for continuing health education and the ‘elimination’ of schistosomiasis (implying a permanent cessation of transmission) often seems a Herculean task. However, the constraining factors are political and economic, not technical. A summary of the current rationale for control and data on its employment are provided in the latest report of the WHO Expert Committee.59 Mollusciciding The use of molluscicides in the control of schistosomiasis is a highly specialized field. Synthetic chemical molluscicides are nowadays primarily restricted to one compound, niclosamide (Bayluscide; Bayer) and, although other chemicals lethal to snails exist, their practical use is minimal. Although many molluscicides of plant origin are known, isolation, characterization, toxicological screening, large-scale production and distribution of their active ingredients for use in endemic countries has not yet proven a viable alternative. A useful specialist text on indications, technical use, application in different habitats and evaluation of molluscicides has been produced by the WHO.280 Molluscicides will continue in use as one of the integral specific control tools, but techniques have changed markedly from the old ‘blanket application’, evolving to a much more



52  Schistosomiasis

focused approach guided by the epidemiological criteria of high prevalence, high intensity and rapidity of reinfection in any particular focus or area of infection.273 Vaccines and Vaccination An anti-schistosomal vaccine is far from being a reality, in that no anti-schistosomal vaccine formulation has proven capable of providing complete (100%) immunity to infection. A comprehensive review of the current status of anti-Schistosoma vaccines has been recently published.281 Whereas advances in molecular biology have led to the identification and characterization of an impressive number of antischistosome vaccine candidate antigens, progress in human vaccination studies has lagged far behind studies in animal models. One limiting feature is that any of the current vaccines, even those with long-term protective effects, will probably be insufficient as a sole control mechanism and will need to be given in conjunction with chemotherapy and other control methods.282,283 The case against such vaccine development has been reviewed in detail elsewhere.284 Presently, the biologically relevant molecules selected as candidates for schistosomal vaccine development are: a variant of

725

the isoenzyme glutathione S-transferase (Sm28GST); paramyosin (Sm97); an irradiation-associated vaccine antigen (IrV-5); the glycolytic enzyme triose-phosphate isomerase (TPI); the membrane antigen Sm23 and a fatty acid-binding protein (FABP) 14 (Sm14).284 However, recent independent testing of these six antigens by two laboratories experienced in experimental schistosomiasis research showed that the modest goal of consistent induction of 40% protection or better was not reached with any of these vaccine candidate molecules tested in mice.283 Currently, the only vaccine candidate molecule undergoing human trials is the glutathione S-transferase (Sh28GST) antigen tested for prevention of S. haematobium infection, although a vaccine containing the extracellular domain of the tetraspanin Sm-TSP-2 is about to undergo clinical testing in Brazil.285 There remain many unanswered questions on the immunology of schistosomiasis and on the mechanisms of protection when it exists and formidable challenges lie ahead regarding large-scale antigen production and the improvement of the modest levels of protection achieved to date in animal models. It will be some years before human vaccines evolve from the present enthusiastic hopes to realistic practical usage in the field.

REFERENCES 1. WHO. Preventive Chemotherapy Databank 2011. Online. Available: http://www.who.int/ neglected_diseases/preventive_chemotherapy/ databank/en/index.html. 2. Rollinson D, Southgate V. The genus Schistosoma: a taxonomic appraisal. In: Rollinson D, Simpson AJ, editors. The Biology of Schistosomes from Genes to Latrines. London: Academic Press; 1987. p. 1–3. 3. King CH. Epidemiology of schistosomiasis: Determinants of transmission of infection. In: Mahmoud AAF, editor. Schistosomiasis.

London: Imperial College Press; 2001. p. 115–32. 11. King CH, Dangerfield-Cha M. The unacknowledged impact of chronic schistosomiasis. Chronic Illn 2008;4(1):65–79. 98. Friedman JF, Kanzaria HK, McGarvey ST. Human schistosomiasis and anemia: the relationship and potential mechanisms. Trends Parasitol 2005;21(8):386–92. 114. Ross AG, Vickers D, Olds GR, et al. Katayama syndrome. Lancet Infect Dis 2007;7(3):218– 24.

285. Hotez PJ, Bethony JM, Diemert DJ, et al. Developing vaccines to combat hookworm infection and intestinal schistosomiasis. Nat Rev Microbiology 2010;8:814–26.

Access the complete references online at www.expertconsult.com

52  Schistosomiasis 725.e1

REFERENCES 1. WHO. Preventive Chemotherapy Databank 2011. Online. Available: http://www.who.int/ neglected_diseases/preventive_chemotherapy/ databank/en/index.html. 2. Rollinson D, Southgate V. The genus Schistosoma: a taxonomic appraisal. In: Rollinson D, Simpson AJ, editors. The Biology of Schistosomes from Genes to Latrines. London: Academic Press; 1987. p. 1–3. 3. King CH. Epidemiology of schistosomiasis: Determinants of transmission of infection. In: Mahmoud AAF, editor. Schistosomiasis. London: Imperial College Press; 2001. p. 115– 32. 4. Bruun B, Aagaard-Hansen J. The Social Context of Schistosomiasis and Its Control. Geneva: World Health Organization; 2008. 5. Ugbomoiko US, Ofoezie IE, Okoye IC, et al. Factors associated with urinary schistosomiasis in two peri-urban communities in southwestern Nigeria. Ann Trop Med Parasitol 2010; 104(5):409–19. 6. Barbosa CS, Araujo KC, Sevilla MA, et al. Current epidemiological status of schistosomiasis in the state of Pernambuco, Brazil. Mem Inst Oswaldo Cruz 2010;105(4):549–54. 7. Kalipeni E, Oppong J. The refugee crisis in Africa and implications for health and disease: a political ecology approach. Soc Sci Med 1998;46(12):1637–53. 8. Carabin H, Marshall CM, Joseph L, et al. Estimating the intensity of infection with Schistosoma japonicum in villagers of Leyte, Philippines. Part I: A Bayesian cumulative logit model. The Schistosomiasis Transmission and Ecology Project (STEP). Am J Trop Med Hyg 2005;72(6):745–53. 9. Savioli L, Hatz C, Dixon H, et al. Control of morbidity due to Schistosoma haematobium on Pemba Island: egg excretion and hematuria as indicators of infection. Am J Trop Med Hyg 1990;43:289–95. 10. de Vlas SJ, Gryseels B, van Oortmarssen GJ, et al. A pocket chart to estimate true Schistosoma mansoni prevalences. Parasitol Today 1993;9(8):305–7. 11. King CH, Dangerfield-Cha M. The unacknowledged impact of chronic schistosomiasis. Chronic Illn 2008;4(1):65–79. 12. King CH, Dickman K, Tisch DJ. Reassessment of the cost of chronic helmintic infection: a meta-analysis of disability-related outcomes in endemic schistosomiasis. Lancet 2005;365: 1561–9. 13. Stothard JR, Chitsulo L, Kristensen TK, et al. Control of schistosomiasis in sub-Saharan Africa: progress made, new opportunities and remaining challenges. Parasitology 2009;136 (13):1665–75. 14. Stothard JR, Sousa-Figuereido JC, Betson M, et al. Schistosoma mansoni infections in young children: when are schistosome antigens in urine, eggs in stool and antibodies to eggs first detectable? PLoS Negl Trop Dis 2011;5(1):e938. 15. Steinmann P, Keiser J, Bos R, et al. Schistosomiasis and water resources development: systematic review, meta-analysis and estimates of people at risk. Lancet Infect Dis 2006;6(7): 411–25. 16. Zhu HM, Xiang S, Yang K, et al. Three Gorges Dam and its impact on the potential transmission of schistosomiasis in regions along the Yangtze River. Ecohealth 2008;5(2):137–48.

17. Bustinduy AL, King CH. Parasitic Helminths. In: Fratamico PM, Smith JL, Brogden KA, editors. Post-infectious Sequelae and LongTerm Consequences of Infectious Diseases. Washington: American Society for Microbiology Press; 2009. p. 291–329. 18. Chen MG, Mott KE. Progress in assessment of morbidity due to Schistosoma haematobium infection. Trop Dis Bull 1989;86:R1–36. 19. Smith J, Christie JD. The pathobiology of Schistosoma haematobium in humans. Hum Pathol 1986;17:333–45. 20. King CH. Long-term outcomes of schoolbased treatment for control of urinary schistosomiasis: a review of experience in Coast Province, Kenya. Mem Inst Oswaldo Cruz 2006;101(Suppl 1):299–306. 21. Warren KS. The pathology, pathobiology and pathogenesis of schistosomiasis. Nature 1978; 273(5664):609–12. 22. Siongok TKA, Ouma JH, Houser HB, et al. Quantification of infection with Schistosoma haematobium in relation to epidemiology and selective population chemotherapy. II Mass treatment with a single oral dose of metrifonate. J Infect Dis 1978;138:856–8. 23. WHO. Prevention and control of schistosomiasis and soil-transmitted helminthiasis: report of a WHO expert committee. Technical Report Series 912. Geneva: World Health Organization; 2002. 24. Bosompem KM, Bentum IA, Otchere J, et al. Infant schistosomiasis in Ghana: a survey in an irrigation community. Trop Med Int Health 2004;9(8):917–22. 25. Odogwu SE, Ramamurthy NK, Kabatereine NB, et al. Schistosoma mansoni in infants (aged <3 years) along the Ugandan shoreline of Lake Victoria. Ann Trop Med Parasitol 2006;100(4):315–26. 26. Cheng TH. Shistosomiasis in mainland China. A review of research and control programs since 1949. Am J Trop Med Hyg 1971;20(1): 26–53. 27. Carabin H, Balolong E, Joseph L, et al. Estimating sensitivity and specificity of a faecal examination method for Schistosoma japonicum infection in cats, dogs, water buffaloes, pigs and rats in Western Samar and Sorsogon Provinces, The Philippines. Int J Parasitol 2005;35 (14):1517–24. 28. Su ZW, Hu CQ, Fu Y, et al. [Role of several hosts in transmission of Schistosomiasis japonica in lake region]. Zhongguo Ji Sheng Chong Xue Yu Ji Sheng Chong Bing Za Zhi 1994;12(1):48–51. 29. Wang L, Utzinger J, Zhou XN. Schistosomiasis control: experiences and lessons from China. Lancet 2008;372(9652):1793–5. 30. Fenwick A. Baboons as reservoir hosts of Schistosoma mansoni. Trans R Soc Trop Med Hyg 1969;63(5):557–67. 31. Rollinson D, Imbert-Establet D, Ross GC. Schistosoma mansoni from naturally infected Rattus rattus in Guadeloupe: identification, prevalence and enzyme polymorphism. Parasitology 1986;93(Pt 1):39–53. 32. Combes C, Imbert-Establet D. Infectivity in rodents of Schistosoma mansoni cercariae of human and murine origin. J Helminthol 1980; 54(3):167–71. 33. Matsumoto J, Muth S, Socheat D, et al. The first reported cases of canine schistosomiasis

mekongi in Cambodia. Southeast Asian J Trop Med Public Health 2002;33(3):458–61. 34. Farooq M. Historical development. In: Epidemiology and Control of Schistosomiasis (Bilharziasis). Basle: Karger; 1973. p. 1–16. 35. Ruffer MA. Note on the presence of Bilharzia haematobia in Egyptian mummies of the 20th dynasty 1220–000 BC. BMJ 1910;i:16. 36. Larrey DJ. (Haematurie) Mémoires de Chirurgie Militaire et Campagnes. Paris: Smith; 1812. 37. Bilharz TM. Fernere Beobachtungun uber das die Pfortader des Menschen bewohnende Distomum haematobium und sein verhaltniss zu gewissen pathologischen Bildungen aus brieflichen Mitheilungen an Professor v. Siebold vom 29 Marz 1852. Acta Tropica 1852;4:72–6. 38. Manson P. Report of a case of bilharzia from the West Indies. BMJ 1902;ii:1894–5. 39. Leiper RT. Researches on Egyptian Bilharziosis. (A report to the War Office on the results of the Bilharzia Mission in Egypt, 1915) Reprinted from JR Army Medical Corps 1915;XXV:1, 147, 253; 1916;XXVII:171; 1918;XXX:235. London: John Bale Sons and Danielson; 1918. 40. da Silva M. La schistosomose à Bahia. Arch Parasitol 1908;13:231–302. 41. Soto VR. Naturateza de la disenteria en Caracas. Doctoral thesis 1906. 42. Fujii Y. Chugai Iji Shimpo [in Japanese] 1847;691:55. 43. Katsurada F. Schistosomum japonicum, a new parasite of man by which an endemic disease in various areas of Japan is caused. Annot Zool Japan 1904;5:146–60. 44. Leiper RT, Atkinson EL. Observations of the spread of Asiatic schistosomiasis. Chin Med J 1915;29:143–9. 45. Logan OT. Three cases of infection with Schistosoma japonicum in Chinese subjects. J Trop Med Hyg 1906;9:294–6. 46. Woolley PG. The occurrence of schistosomiasis japonicum vel cattoi in the Philippine islands. Phillipine J Sci 1906;1:83–90. 47. Brug SL, Tesch JW. Parasitic worm infestations in inhabitants around Lake Lindoe, Celebes. Geneeskd T Ned Ind 1937;77:2151–8. 48. Faust EC, Meleney HE. Studies on schistosomiasis japonica. With a supplement on the molluscan hosts of the human blood fluke in China and Japan and species liable to be confused with them, by Nelson Anandale. Am J Hyg (Monogr Ser) 1924;3:1–139. 49. Tubangui MA. The molluscan intermediate host in the Phillipines of the oriental blood fluke Schistosoma japonicum. Philippine J Sci 1932;49:295–304. 50. Chesterman CC. Note sur la bilharziose dans la region de Stanleyville (Congo Belge). Ann Soc Belg Méd Trop 1923;3:73. 51. Fisher AC. A study of the schistosomiasis of the Stanleyville district of the Belgian Congo. Trans R Soc Trop Med Hyg 1934;28:277–306. 52. Pages JR, Jourdane J, Southgate VR, et al. Reconnaissance deux especes jumelles au sein du taxon Schistosoma intercalatum Fisher 1934, agent de la schistosome humaine rectale en Afrique. N. sp. Taxonomy, Ecology and Evolution of Metazoan Parasites. Perpignan: Presses Universitaires de Perpignan; 2003. 53. Webster BL, Southgate VR, Littlewood DT. A revision of the interrelationships of Schistosoma including the recently described

725.e2 SECTION 10 

Helminthic Infections

Schistosoma guineensis. Int J Parasitol 2006;36: 974–55. 54. Voge M, Bruckner D, Bruce JI. Schistosoma mekongi sp. n. from man and animals, compared with four geographic strains of Schis­ tosoma japonicum. J Parasitol 1978;64(4): 577–84. 55. Bruce JI, Sornmani S, Asch HL, et al. The Mekong Schistosome. Malacol Rev 1980;(Suppl 2):1–282. 56. Woodruff DS, Merenlender AM, Upatham ES, et al. Genetic variation and differentiation of three Schistosoma species from the Philippines, Laos and Peninsular Malaysia. Am J Trop Med Hyg 1987;36(2):345–54. 57. Greer GJ, Ow-Yang CK, Yong HS. Schistosoma malayensis n. sp.: a Schistosoma japonicumcomplex schistosome from Peninsular Malaysia. J Parasitol 1988;74(3):471–80. 58. Upatham ES, Kruatrachue M, Viyanant V, et al. Biology of Robertsiella kaporensis snails and Malaysian Schistosoma. Southeast Asian J Trop Med Public Health 1985;16(1):1–9. 59. Savioli L, Gabrielli AF, Montresor A, et al. Schistosomiasis control in Africa: 8 years after World Health Assembly Resolution 54.19. Parasitology 2009;136(13):1677–81. 60. Amarir F, El Mansouri B, Fellah H, et al. National serologic survey of Haematobium schistosomiasis in Morocco: evidence for elimination. Am J Trop Med Hyg 2011;84(1): 15–19. 61. Amaral RS, Tauil PL, Lima DD, et al. An analysis of the impact of the Schistosomiasis Control Programme in Brazil. Mem Inst Oswaldo Cruz 2006;101(Suppl 1):79–85. 62. Doumenge JP, Mott KE, Cheung C, et al. Atlas de la Répartition Mondiale des Schistosomiases. Geneva: CEGET-CRNS: WHO; 1987. 63. Chitsulo L, Engels D, Montresor A, et al. The global status of schistosomiasis and its control. Acta Trop 2000;77(1):41–51. 64. Chitsulo L, Loverde P, Engels D. Schistosomiasis. Nat Rev Microbiol 2004;2(1):12–13. 65. King CH. Disease due to Schistosoma mekongi, S. intercalatum and Other Schistosome Species. In: Mahmoud AAF, editor. Schistosomiasis. London: Imperial College Press; 2001. p. 391– 412. 66. Nelson GS, Amin MA, Saoud MF, et al. Studies on heterologous immunity in schistosomiasis. I. Heterologous schistosome immunity in mice. Bull World Health Organ 1968;38(1): 9–17. 67. Lindblade KA. The epidemiology of cercarial dermatitis and its association with limnological characteristics of a northern Michigan lake. J Parasitol 1998;84(1):19–23. 68. Satayathum SA, Muchiri EM, Ouma JH, et al. Factors affecting infection or reinfection with Schistosoma haematobium in coastal Kenya: survival analysis during a nine-year, schoolbased treatment program. Am J Trop Med Hyg 2006;75(1):83–92. 69. Christopherson JB. Longevity of parasitic worms. The term of living existence of Schistosoma haematobium in the human body. Lancet 1924:742–3. 70. Chabasse D, Bertrand G, Leroux JP, et al. [Developmental bilharziasis caused by Schistosoma mansoni discovered 37 years after infestation]. Bull Soc Pathol Exot Filiales 1985;78 (5):643–7. 71. Anderson RM, May RM. Infectious diseases of humans. Dynamics and Control. New York: Oxford University Press; 1991.

72. Ouma JH, Vennervald BJ, Butterworth AE. Morbidity in schistosomiasis: an update. Trends Parasitol 2001;17(3):117–18. 73. Smith JH, Kamel IA, Elwi A, et al. A quan­ titative post mortem analysis of urinary schistosomiasis in Egypt. I. Pathology and pathogenesis. Am J Trop Med Hyg 1974; 23(6):1054–71. 74. Rumjanek F. Biochemistry and physiology. In: Rollinson D, Simpson AJ, editors. The Biology of Schistosomes from Genes to Latrines. London: Academic Press; 1987. p. 1–3. 75. Wilson RA. Cercariae to liver worms: development and migration in the mammalian host. In: Rollinson D, Simpson AJ, editors. The Biology of Schistosomes from Genes to Latrines. London: Academic Press; 1987. 76. Hairston N. The dynamics of transmission. In: Ansari N, editor. Epidemiology and Con­ trol of Schistosomiasis. Basle: Karger; 1973. p. 32–249. 77. Wright W. Geographical distribution of schistosomes and their intermediate hosts. In: Ansari N, editor. Epidemiology and Control of Schistosomiasis. Basle: Karger; 1973. p. 32– 249. 78. Theron A, Mone H. Chronobiological aspects of the host-parasite relationships between Biomphalaria glabrata and Schistosoma mansoni: cercarial production and infectivity and growth kinetics of the host. J Invertebr Pathol 1984;44(2):209–13. 79. Sturrock BM. The effect of infection with Schistosoma haematobium on the growth and reproduction rates of Bulinus (Physopsis) nasutus productus. Ann Trop Med Parasitol 1967;61(3):321–5. 80. Stothard IR, Rollinson D. Molecular characterization of Bulinus globosus and B. nasutus on Zanzibar and an investigation of their roles in the epidemiology of Schistosoma haematobium. Trans R Soc Trop Med Hyg 1997;91 (3):353–7. 81. Southgate V, Rollinson D. Natural history of transmission and interactions. In: Rollinson D, Simpson AJ, editors. The Biology of Schistosomes from Genes to Latrines. London: Academic Press; 1987. 82. Pesigan TP, Farooq M, Hairston NG, et al. Studies on Schistosoma japonicum infection in the Philippines. 1. General considerations and epidemiology. Bull World Health Organ 1958;18(3):345–455. 83. Pesigan TP, Hairston NG, Jauregui JJ, et al. Studies on Schistosoma japonicum infection in the Philippines. 2. The molluscan host. Bull World Health Organ 1958;18(4):481–578. 84. Zhou XN, Yang GJ, Yang K, et al. Potential impact of climate change on schistosomiasis transmission in China. Am J Trop Med Hyg 2008;78(2):188–94. 85. Loker ES. Research on the Molluscan Intermediate Hosts for Schistosomiasis: What are the Priorities? Geneva: World Health Organization; 2005. 86. Sturrock RF, Karamsadkar SJ, Ouma J. Schistosome infection rates in field snails: Schistosoma mansoni in Biomphalaria pfeifferi from Kenya. Ann Trop Med Parasitol 1979;73(4): 369–75. 87. Shane HL, Verani JR, Abudho B, et al. Evaluation of urine CCA assays for detection of Schistosoma mansoni infection in western Kenya. PLoS Negl Trop Dis 2011;5:e591. 88. King CL, Malhotra I, Mungai P, et al. B cell sensitization to helminthic infection develops

in utero in humans. J Immunol 1998;160(7): 3578–84. 89. Caldas IR, Campi-Azevedo AC, Oliveira LF, et al. Human schistosomiasis mansoni: immune responses during acute and chronic phases of the infection. Acta Trop 2008;108 (2–3):109–17. 90. Li Y, Rabello AL, Simpson AJ, et al. The serological differentiation of acute and chronic Schistosoma japonicum infection by ELISA using keyhole limpet haemocyanin as antigen. Trans R Soc Trop Med Hyg 1994;88(2):249– 51. 91. King CL, et al. Cytokine control of parasitespecific anergy in human urinary schistosomiasis. IL-10 modulates lymphocyte reactivity. J Immunol 1996;156(12):4715–21. 92. Wamachi AN, Mayadev JS, Mungai PL, et al. Increased ratio of tumor necrosis factor-alpha to interleukin-10 production is associated with Schistosoma haematobium-induced urinarytract morbidity. J Infect Dis 2004;190(11): 2020–30. 93. Woolhouse MEJ. Patterns in parasite epidemiology: The peak shift. Parasitol Today 1998;14 (10):428–34. 94. Coutinho HM, Acosta LP, Wu HW, et al. Th2 cytokines are associated with persistent hepatic fibrosis in human Schistosoma japonicum infection. J Infect Dis 2007;195(2): 288–95. 95. Coutinho HM, Leenstra T, Acosta LP, et al. Proinflammatory cytokines and C-reactive protein are associated with undernutrition in the context of Schistosoma japonicum infection. Am J Trop Med Hyg 2006;75(4):720–6. 96. Leenstra T, Acosta LP, Langdon GC, et al. Schistosomiasis japonica, anemia and iron status in children, adolescents and young adults in Leyte, Philippines. Am J Clin Nutr 2006;83 (2):371–9. 97. Koukounari A, Fenwick A, Whawell S, et al. Morbidity indicators of Schistosoma mansoni: relationship between infection and anemia in Ugandan schoolchildren before and after praziquantel and albendazole chemotherapy. Am J Trop Med Hyg 2006;75(2):278–86. 98. Friedman JF, Kanzaria HK, McGarvey ST. Human schistosomiasis and anemia: the relationship and potential mechanisms. Trends Parasitol 2005;21(8):386–92. 99. Hagan P, Blumenthal UJ, Dunn D, et al. Human IgE, IgG4 and resistance to reinfection with Schistosoma haematobium. Nature 1991;349 (6306):243–5. 100. Correa-Oliveira R, Caldas IR, Gazzinelli G. Natural versus drug-induced resistance in Schistosoma mansoni infection. Parasitol Today 2000;16(9):397–9. 101. Wilkins HA, Goll PH, Marshall TF, et al. Dynamics of Schistosoma haematobium infection in a Gambian community. I. The pattern of human infection in the study area. Trans R Soc Trop Med Hyg 1984;78(2): 216–21. 102. Goll PH, Wilkins HA, Marshall TF. Dynamics of Schistosoma haematobium infection in a Gambian community. II. The effect on transmission of the control of Bulinus senegalensis by the use of niclosamide. Trans R Soc Trop Med Hyg 1984;78(2):222–6. 103. Wilkins HA, Goll PH, Marshall TF, et al. Dynamics of Schistosoma haematobium infection in a Gambian community. III. Acquisition and loss of infection. Trans R Soc Trop Med Hyg 1984;78(2):227–32.

52  Schistosomiasis 725.e3

104. Butterworth AE, Hagan P. Immunity in human schistosomiasis. Parasitol Today 1987;3(1): 11–16. 105. Hagan P. Reinfection, exposure and immunity in human schistosomiasis. Parasitol Today 1992;8(1):12–16. 106. Blanton RE, Salam EA, Ehsan A, et al. Schistosomal hepatic fibrosis and the interferon gamma receptor: a linkage analysis using single-nucleotide polymorphic markers. Eur J Hum Genet 2005;13:660–8. 107. Dessein AJ, Hillaire D, Elwali NE, et al. Severe hepatic fibrosis in Schistosoma mansoni infection is controlled by a major locus that is closely linked to the interferon-gamma receptor gene. Am J Hum Genet 1999;65(3): 709–21. 108. LaBeaud AD, Malhotra I, King MJ, et al. Do antenatal parasite infections devalue childhood vaccination? PLoS Negl Trop Dis 2009; 3(5):e442. 109. Malhotra I, Mungai P, Wamachi A, et al. Helminth- and Bacillus Calmette-Guerin-induced immunity in children sensitized in utero to filariasis and schistosomiasis. J Immunol 1999; 162(11):6843–8. 110. Stothard JR, Kabatereine NB, Tukahebwa EM, et al. Use of circulating cathodic antigen (CCA) dipsticks for detection of intestinal and urinary schistosomiasis. Acta Trop 2006;97(2):219–28. 111. Cheever A, Kamel IA, Elwi AM, et al. Schistosoma mansoni and S. haematobium infections in Egypt. II. Quantitative parasitological findings at necropsy. Am J Trop Med Hyg 1977;26:702–16. 112. Naus CW, van Dam GJ, Kremsner PG, et al. Human IgE, IgG subclass and IgM responses to worm and egg antigens in schistosomiasis haematobium: a 12-month study of reinfection in Cameroonian children. Clin Infect Dis 1998;26(5):1142–7. 113. Mulvihill CA, Burnett JW. Swimmer’s itch: a cercarial dermatitis. Cutis 1990;46(3):211–13. 114. Ross AG, Vickers D, Olds GR, et al. Katayama syndrome. Lancet Infect Dis 2007;7(3): 218–24. 115. Ross AG, Sleigh AC, Li Y, et al. Schistosomiasis in the People’s Republic of China: prospects and challenges for the 21st century. Clin Microbiol Rev 2001;14(2):270–95. 116. Abdel-Salam E, Ehsan A. Cystoscopic picture of Schistosoma haematobium in Egyptian children correlated to intensity of infection and morbidity. Am J Trop Med Hyg 1978; 27(4):774–8. 117. Farid Z. Chronic urinary Salmonella carriers with intermittent bacteraemia. J Egypt Public Health Assoc 1970;45(1):157–60. 118. Leutscher P, Ramarokoto CE, Reimert C, et al. Community-based study of genital schistosomiasis in men from Madagascar. Lancet 2000; 355(9198):117–18. 119. Leutscher PD, Host E, Reimert CM. Semen quality in Schistosoma haematobium infected men in Madagascar. Acta Trop 2009;109(1): 41–4. 120. Kjetland EF, Ndhlovu PD, Mduluza T, et al. Simple clinical manifestations of genital Schistosoma haematobium infection in rural Zimbabwean women. Am J Trop Med Hyg 2005; 72(3):311–19. 121. El-Mahgoub S. Pelvic schistosomiasis and infertility. Int J Gynaecol Obstet 1982;20(3): 201–6. 122. Kjetland EF, Kurewa EN, Mduluza T, et al. The first community-based report on the effect of

123.

124.

125.

126.

127.

128. 129. 130.

131.

132.

133.

134.

135.

136. 137. 138. 139. 140. 141.

genital Schistosoma haematobium infection on female fertility. Fertil Steril 2010;94(4): 1551–3. Higashi GI, Abdel-Salam E, Soliman M, et al. Immunofluorescent analysis of renal biopsies in uncomplicated Schistosoma haematobium infections in children. J Trop Med Hyg 1984;87(3):123–9. Sadigursky M, andrade ZA, Danner R, et al. Absence of schistosomal glomerulopathy in Schistosoma haematobium infection in man. Trans R Soc Trop Med Hyg 1976;70(4): 322–3. Farid Z, Higashi GI, Bassily S, et al. Chronic salmonellosis, urinary schistosomiasis and massive proteinuria. Am J Trop Med Hyg 1972;21(5):578–81. Nafeh MA, Medhat A, Swifae Y, et al. Ultrasonographic changes of the liver in Schistosoma haematobium infection. Am J Trop Med Hyg 1992;47(2):225–30. Scrimgeour EM, Gajdusek DC. Involvement of the central nervous system in Schistosoma mansoni and S. haematobium infection. A review. Brain 1985;108(Pt 4):1023–38. van der Horst R. Schistosomiasis of the pericardium. Trans R Soc Trop Med Hyg 1979; 73(2):243–4. Chitiyo ME. Schistosomal involvement of the choroid plexus. Cent Afr J Med 1972;18(3): 45–7. WHO. International Agency for Research on Cancer: Monographs on the Evaluation of Carcinogenic Risks to Humans. Schistosomes, Liver Flukes and Helicobacter pylori. Geneva: WHO; 1997. Hicks RM, James C, Webbe G. Effect of Schistosoma haematobium and N-butyl-N-(4hydroxybutyl)nitrosamine on the development of urothelial neoplasia in the baboon. Br J Cancer 1980;42(5):730–55. Schwartz DA. Helminths in the induction of cancer II. Schistosoma haematobium and bladder cancer. Trop Geogr Med 1981;33(1): 1–7. Kuntz RE, Cheever AW, Myers BJ. Proliferative epithelial lesions of the urinary bladder of nonhuman primates infected with Schistosoma haematobium. J Natl Cancer Inst 1972; 48(1):223–35. Hicks RM, Ismail MM, Walters CL, et al. Association of bacteriuria and urinary nitrosamine formation with Schistosoma haematobium infection in the Qalyub area of Egypt. Trans R Soc Trop Med Hyg 1982;76(4):519–27. Mostafa MH, Sheweita SA, O’Connor PJ. Relationship between schistosomiasis and bladder cancer. Clin Microbiol Rev 1999;12(1):97– 111. Chen M, Mott, KE. Progress in the assessment of morbidity due to Schistosoma mansoni infection. Trop Dis Bull 1988;85:R1–56. Warren KS. The kinetics of hepatosplenic schistosomiasis. Semin Liver Dis 1984;4(4): 293–300. Dunn MA, Kamel R. Hepatic schistosomiasis. Hepatology 1981;1(6):653–61. Dunn MA. Liver collagen synthesis and degradation in schistosomiasis. Contrib Microbiol Immunol 1983;7:198–203. Warren KS. The relevance of schistosomiasis. N Engl J Med 1980;303(4):203–6. Lambertucci JR, Voieta I, Andrade LM. Gamna-Gandy bodies in hepatosplenic schistosomiasis mansoni. Rev Soc Bras Med Trop 2008;41(3):320–1.

142. Andrade ZA, Abreu WN. Follicular lymphoma of the spleen in patients with hepatosplenic schistosomiasis mansoni. Am J Trop Med Hyg 1971;20(2):237–43. 143. Barsoum RS, Bassily S, Soliman MM, et al. Renal amyloidosis and schistosomiasis. Trans R Soc Trop Med Hyg 1979;73(4):367–74. 144. Pittella JE, Lana-Peixoto MA. Brain involvement in hepatosplenic schistosomiasis mansoni. Brain 1981;104(3):621–32. 145. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 21–1985. A 21-year-old man with fever, diarrhea and weakness of the legs during a sojourn in Kenya. N Engl J Med 1985;312 (21):1376–83. 146. Bittencourt AL, Cardoso de Almeida MA, Iunes MA, et al. Placental involvement in schistosomiasis mansoni. Report of four cases. Am J Trop Med Hyg 1980;29(4):571–5. 147. Chen MG. Relative distribution of Schistosoma japonicum eggs in the intestine of man: a subject of inconsistency. Acta Trop 1991;48 (3):163–71. 148. Santos AT. The present status of schistosomiasis in the Philippines. Southeast Asian J Trop Med Public Health 1984;15(4):439–45. 149. Mao S, He YX, Yang YQ, et al. Schistosoma japonicum and schistosomiasis japonica. (in Chinese). Chinese Medical Encyclopaedia, Parasitology and Parasitic Diseases. Shanghai: Shanghai Publishing House for Sciences and Technology; 1984. p. 44–55. 150. Garin D, Chapalain JC, Thierry J, et al. [Focus on Schistosoma intercalatum]. Med Trop (Mars) 1990;50(4):433–40. 151. Simarro PP, Sima FO, Mir M. Urban epidemiology of Schistosoma intercalatum in the city of Bata, Equatorial Guinea. Trop Med Parasitol 1990;41(3):254–6. 152. Bustinduy AL, Thomas CL, Fiutem JJ, et al. Measuring fitness of Kenyan children with polyparasitic infections using the 20-meter shuttle run test as a morbidity metric. PLoS Negl Trop Dis 2011;5(7):e1213. 153. Friedman JF, Kanzaria HK, Acosta LP, et al. Relationship between Schistosoma japonicum and nutritional status among children and young adults in Leyte, the Philippines. Am J Trop Med Hyg 2005;72(5):527–33. 154. Giboda M, Bergquist NR. Post-transmission schistosomiasis. Parasitol Today 1999;15(8): 307–8. 155. King CH. Parasites and poverty: the case of schistosomiasis. Acta Trop 2010;113(2): 95–104. 156. Soleng A, Mehl R. Geographical distribution of cercarial dermatitis in Norway. J Helminthol 2011;85(3):345–52. 157. Farahnak A, Essalat M. A study on cercarial dermatitis in Khuzestan province, south western Iran. BMC Public Health 2003;3:35. 158. Bottieau E, Clerinx J, de Vega MR, et al. Imported Katayama fever: clinical and biological features at presentation and during treatment. J Infect 2006;52(5):339–45. 159. Koukounari A, Estambale BB, Njagi JK, et al. Relationships between anaemia and parasitic infections in Kenyan schoolchildren: a Bayesian hierarchical modelling approach. Int J Parasitol 2008;38(14):1663–71. 160. Nemeth E, Rivera S, Gabayan V, et al. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest 2004;113 (9):1271–6.

725.e4 SECTION 10 

Helminthic Infections

161. Ezeamama AE, Friedman JF, Acosta LP, et al. Helminth infection and cognitive impairment among Filipino children. Am J Trop Med Hyg 2005;72(5):540–8. 162. Stephenson LS, Latham MC, Kurz KM, et al. Urinary iron loss and physical fitness of Kenyan children with urinary schistosomiasis. Am J Trop Med Hyg 1985;34(2):322–30. 163. Gurarie D, Wang X, Bustinduy AL, et al. Modeling the effect of chronic schistosomiasis on childhood development and the potential for catch-up growth with different drug treatment strategies promoted for control of endemic schistosomiasis. Am J Trop Med Hyg 2011; 84(5):773–81. 164. Coutinho HM, McGarvey ST, Acosta LP, et al. Nutritional status and serum cytokine profiles in children, adolescents and young adults with Schistosoma japonicum-associated hepatic fibrosis, in Leyte, Philippines. J Infect Dis 2005;192(3):528–36. 165. Assis AM, Prado MS, Barreto ML, et al. Childhood stunting in Northeast Brazil: the role of Schistosoma mansoni infection and inadequate dietary intake. Eur J Clin Nutr 2004; 58(7):1022–9. 166. McGarvey ST, Zhou XN, Willingham 3rd AL, et al. The epidemiology and host-parasite relationships of Schistosoma japonicum in definitive hosts. Parasitol Today 1999;15(6): 214–15. 167. Stephenson LS, Latham MC, Kurz KM, et al. Single dose metrifonate or praziquantel treatment in Kenyan children. II. Effects on growth in relation to Schistosoma haematobium and hookworm egg counts. Am J Trop Med Hyg 1989;41(4):445–53. 168. Parraga IM, Assis AM, Prado MS, et al. Gender differences in growth of school-aged children with schistosomiasis and geohelminth infection. Am J Trop Med Hyg 1996;55(2): 150–6. 169. Nokes C, McGarvey ST, Shiue L, et al. Evidence for an improvement in cognitive function following treatment of Schistosoma japonicum infection in Chinese primary schoolchildren. Am J Trop Med Hyg 1999;60(4):556–65. 170. Jukes MC, Nokes CA, Alcock KJ, et al. Heavy schistosomiasis associated with poor shortterm memory and slower reaction times in Tanzanian schoolchildren. Trop Med Int Health 2002;7(2):104–17. 171. Nazel MW, el-Morshedy H, Farghaly A, et al. Schistosoma mansoni infection and cognitive functions of primary school children, in Kafr El Sheikh, Egypt. J Egypt Public Health Assoc 1999;74(1–2):97–119. 172. Koukounari A, Gabrielli AF, Toure S, et al. Schistosoma haematobium infection and morbidity before and after large-scale administration of praziquantel in Burkina Faso. J Infect Dis 2007;196(5):659–69. 173. Leenstra T, Coutinho HM, Acosta LP, et al. Schistosoma japonicum reinfection after praziquantel treatment causes anemia associated with inflammation. Infect Immun 2006;74 (11):6398–407. 174. Singer BH, Ryff CD. Neglected tropical diseases, neglected data sources and neglected issues. PLoS Negl Trop Dis 2007;1(2):e104. 175. Jamison DT, Breman JG, Measham AR, et al., editors. Disease Control Priorities in Developing Countries. 2nd ed. New York: Oxford University Press; 2006. 176. King CH, Keating CE, Muruka JF, et al. Urinary tract morbidity in schistosomiasis haematobia:

177. 178.

179.

180.

181.

182.

183.

184.

185.

186.

187.

188.

189. 190.

191. 192.

193.

associations with age and intensity of infection in an endemic area of Coast Province, Kenya. Am J Trop Med Hyg 1988;39(4):361–8. Lehman Jr JS, Farid Z, Bassily S. Salmonellosis and schistosomiasis of urinary tract. N Engl J Med 1970;283(23):1291. Higashi GI, Farid Z, Bassily S, et al. Nephrotic syndrome in schistosomiasis mansoni complicated by chronic salmonellosis. Am J Trop Med Hyg 1975;24(4):713–14. Christie JD, Crouse D, Smith JH, et al. Patterns of Schistosoma haematobium egg distribution in the human lower urinary tract. II. Obstructive uropathy. Am J Trop Med Hyg 1986; 35(4):752–8. Kjetland EF, Poggensee G, Helling-Giese G, et al. Female genital schistosomiasis due to Schistosoma haematobium. Clinical and parasitological findings in women in rural Malawi. Acta Trop 1996;62(4):239–55. Kjetland EF, Mduluza T, Ndhlovu PD, et al. Genital schistosomiasis in women: a clinical 12-month in vivo study following treatment with praziquantel. Trans R Soc Trop Med Hyg 2006;100(8):740–52. Downs JA, Mguta C, Kaatano GM, et al. Urogenital schistosomiasis in women of reproductive age in Tanzania’s Lake Victoria region. Am J Trop Med Hyg 2011;84(3):364–9. Feldmeier H, Daccal RC, Martins MJ, et al. Genital manifestations of schistosomiasis mansoni in women: important but neglected. Mem Inst Oswaldo Cruz 1998;93(Suppl 1): 127–33. Arap Siongok TK, Mahmoud AA, Ouma JH, et al. Morbidity in schistosomiasis mansoni in relation to intensity of infection: study of a community in Machakos, Kenya. Am J Trop Med Hyg 1976;25(2):273–84. Cook JA, Baker ST, Warren KS, et al. A controlled study of morbidity of schistosomiasis mansoni in St. Lucian children, based on quantitative egg excretion. Am J Trop Med Hyg 1974;23(4):625–33. Lambertucci JR, Serufo JC, Gerspacher-Lara R, et al. Schistosoma mansoni: assessment of morbidity before and after control. Acta Trop 2000;77(1):101–9. Kamal SM, Graham CS, He Q, et al. Kinetics of intrahepatic hepatitis C virus (HCV)-specific CD4+ T cell responses in HCV and Schistosoma mansoni coinfection: relation to progression of liver fibrosis. J Infect Dis 2004;189(7): 1140–50. Zhou H, Ross AG, Hartel GF, et al. Diagnosis of schistosomiasis japonica in Chinese schoolchildren by administration of a questionnaire. Trans R Soc Trop Med Hyg 1998;92(3): 245–50. Chen MG. Progress and problems in schistosomiasis control in China. Trop Med Parasitol 1989;40(2):174–6. Jusot JF, Simarro PP, De Muynck A. [Schistosoma intercalatum bilharziasis: clinical and epidemiological considerations]. Med Trop (Mars) 1997;57(3):280–8. Corachan M, Escosa R, Mas J, et al. Clinical presentation of Schistosoma intercalatum infestation. Lancet 1987;1(8542):1139–40. Arene FO, Ukpeibo ET, Nwanze EA. Studies on schistosomiasis in the Niger Delta: Schistosoma intercalatum in the urban city of Port Harcourt, Nigeria. Public Health 1989;103(4): 295–301. Braun-Munzinger RA, Southgate BA. Repeatability and reproducibility of egg counts of

194.

195.

196.

197.

198. 199.

200.

201.

202.

203.

204.

205.

206.

207. 208. 209. 210.

211.

Schistosoma haematobium in urine. Trop Med Parasitol 1992;43(3):149–54. Wilson AR, van Dam GJ, Kariuki TM, et al. The detection limits for estimates of infection intensity in schistosomiasis mansoni established by a study in non-human primates. Int J Parasitol 2006;36(12):1241–4. Peters PA, Mahmoud AA, Warren KS, et al. Field studies of a rapid, accurate means of quantifying Schistosoma haematobium eggs in urine samples. Bull World Health Organ 1976;54(2):159–62. Mott KE. A reusable polyamide filter for diagnosis of S. haematobium infection by urine filtration. Bull Soc Pathol Exot Filiales 1983;76(1):101–4. Braun-Munzinger RA, Rohde R. False epidemiological results from the bulk transport of dried filter papers in urinary schistosomiasis. Trop Med Parasitol 1986;37(3):286–9. Ritchie LS. An ether sedimentation technique for routine stool examinations. Bull US Army Med Dep 1948;8(4):326. Knight WB, Hiatt RA, Cline BL, et al. A modification of the formol-ether concentration technique for increased sensitivity in detecting Schistosoma mansoni eggs. Am J Trop Med Hyg 1976;25(6):818–23. Blagg W, Schloegel EL, Mansour NS, et al. A new concentration technic for the demonstration of protozoa and helminth eggs in feces. Am J Trop Med Hyg 1955;4(1):23–8. Visser PS, Pitchford RJ. A simple apparatus for rapid recovery of helminth eggs from excreta with special reference to Schistosoma mansoni. S Afr Med J 1972;46(37):1344–6. Katz N, Chaves A, Pellegrino J. A simple device for quantitative stool thick-smear technique in schistosomiasis mansoni. Rev Inst Med Trop Sao Paulo 1972;14(6):397–400. Komiya Y, Kobayashi A. Evaluation of Kato’s thick smear technic with a cellophane cover for helminth eggs in feces. Jpn J Med Sci Biol 1966;19(1):59–64. Teesdale CH, Amin MA. Comparison of the Bell technique, a modified Kato thick smear technique and a digestion method for the field diagnosis of schistosomiasis mansoni. J Helminthol 1976;50(1):17–20. Teesdale CH, Amin MA. A simple thick-smear technique for the diagnosis of Schistosoma mansoni infection. Bull World Health Organ 1976;54(6):703–5. Chitsulo L, Teesdale CH, Dixon H. Com­ parison of the Teesdale glass sandwich and Kato-Katz techniques for the diagnosis of Schistosoma mansoni: a double-blind study. Trop Med Parasitol 1990;41(4):447–9. Cook JA, Jordan P. Excretion of Schistosoma mansoni ova in the urine. Trans R Soc Trop Med Hyg 1970;64(5):793–4. Fulleborn F. Uber den Nachweis der Schistosomum mansoni: Eir in Stuhle. Arch Schiffs Tropenkr Hamburg 1921;25:334–40. Fun-Zhi. Schistosomiasis Shou Chai. 2nd ed. Shanghai: People’s Press; 1971. Shanghai Municipal Institute for Prevention and Treatment of Schistosomiasis. Handbook on the Prevention and Treatment of Schistosomiasis (translated by the US Department of Health, Education and Welfare, Public Health Service, National Institutes of Health). Shanghai: DHEW; 1977. Gorman S, Meeser CV, et al. The macroscopic diagnosis of urinary schistosomiasis. S Afr Med J 1947;21(842–51 No 22):853.

52  Schistosomiasis 725.e5

212. Weber MC. Miracidal hatching in the diagnosis of bilharziasis. Cent Afr J Med 1973 Sept:11–14. 213. Braun-Munzinger RA, Southgate BA. Egg viability in urinary schistosomiasis. I. New methods compared with available methods. J Trop Med Hyg 1993;96(1):22–7. 214. Braun-Munzinger RA, Southgate BA. Egg viability in urinary schistosomiasis. II. Simplifying modifications and standardization of new methods. J Trop Med Hyg 1993;96(2): 71–5. 215. Braun-Munzinger RA, Southgate BA. Egg viability in urinary schistosomiasis. III. Repeatability and reproducibility of new methods. J Trop Med Hyg 1993;96(3):179–85. 216. Upatham ES, Sturrock RF, Cook JA. Studies on the hatchability of Schistosoma mansoni eggs from a naturally infected human community on St Lucia, West Indies. Parasitology 1976; 73(3):253–64. 217. Zicker F, Katz N, Wolf J. [Evaluation of the hatching test for eggs of Schistosoma mansoni]. Rev Inst Med Trop Sao Paulo 1977;19(3): 202–7. 218. da Cunha AS. [Therapeutic evaluation of oxamniquine in schistosomiasis mansoni by the oogram method with biopsy of rectal mucosa]. Rev Inst Med Trop Sao Paulo 1982; 24(2):88–94. 219. Briggs M, Chadfield M, Mummery D. Screening with reagent strips. BMJ 1971;3(5771): 433–4. 220. Feldmeier H, Doehring E, Daffalla AA. Simultaneous use of a sensitive filtration technique and reagent strips in urinary schistosomiasis. Trans R Soc Trop Med Hyg 1982;76(3): 416–21. 221. Sellin B, Simonkovich E, Ovazza L, et al. [Value of macroscopic urine examination and reagent strips for the detection of hematuria and proteinuria in the mass diagnosis of urinary schistosomiasis, before and after treatment]. Med Trop (Mars) 1982;42(5):521–6. 222. Mott KE, Dixon H. Collaborative study on antigens for immunodiagnosis of schistosomiasis. Bull World Health Organ 1982;60(5): 729–53. 223. Mott KE, Dixon H, Carter CE, et al. Collaborative study on antigens for immunodiagnosis of Schistosoma japonicum infection. Bull World Health Organ 1987;65(2):233–44. 224. Bergquist R, editor. Immunodiagnostic Approaches in Schistosomiasis. London: John Wiley; 1992. 225. Stothard JR, Sousa-Figueiredo JC, Standley C, et al. An evaluation of urine-CCA strip test and fingerprick blood SEA-ELISA for detection of urinary schistosomiasis in schoolchildren in Zanzibar. Acta Trop 2009;111(1):64–70. 226. van Lieshout L, Polderman AM, Deelder AM. Immunodiagnosis of schistosomiasis by determination of the circulating antigens CAA and CCA, in particular in individuals with recent or light infections. Acta Trop 2000;77(1): 69–80. 227. Abdel-Wahab MF, Strickland GT. Abdominal ultrasonography for assessing morbidity from schistosomiasis. 2. Hospital studies. Trans R Soc Trop Med Hyg 1993;87(2):135–7. 228. Hatz C, Jenkins JM, Morrow RH, et al. Ultrasound in schistosomiasis – a critical look at methodological issues and potential applications. Acta Trop 1992;51(1):89–97. 229. WHO. Meeting on ultrasonography in schistosomiasis: Proposal for a practical guide to the

230.

231.

232. 233.

234.

235. 236.

237.

238. 239.

240.

241.

242.

243.

244.

245.

246.

standardized use of ultrasound in the assessment of pathological changes. Geneva: World Health Organization; 1991. Report No.: TDR/ SCH/ULTRASON/91.3. King CH, Olbrych SK, Soon M, et al. Utility of repeated praziquantel dosing in the treatment of schistosomiasis in high-risk communities in Africa: a systematic review. PLoS Negl Trop Dis 2011;5(9):e1321. Ozier O. Exploiting externalities to estimate the long-term effects of early childhood deworming. NBER Working Paper 6 June, 2011. Anonymous. Drugs for parasitic infections. Online. Available: http://secure.medicalletter. org/para 2010;e1–19. Doenhoff MJ, Cioli D, Utzinger J. Praziquantel: mechanisms of action, resistance and new derivatives for schistosomiasis. Curr Opin Infect Dis 2008;21(6):659–67. Duong TH, Furet Y, Lorette G, et al. [Treatment of bilharziasis due to Schistosoma mekongi with praziquantel]. Med Trop (Mars) 1988;48 (1):39–43. King CH, Mahmoud AA. Drugs five years later: praziquantel. Ann Intern Med 1989;110 (4):290–6. Gryseels B, Stelma FF, Talla I, et al. Epidemiology, immunology and chemotherapy of Schistosoma mansoni infections in a recently exposed community in Senegal. Trop Geogr Med 1994;46(4 Spec No):209–19. Guisse F, Polman K, Stelma FF, et al. Therapeutic evaluation of two different dose regimens of praziquantel in a recent Schistosoma mansoni focus in Northern Senegal. Am J Trop Med Hyg 1997;56(5):511–14. Utzinger J, Xiao SH, Tanner M, et al. Artemisinins for schistosomiasis and beyond. Curr Opin Investig Drugs 2007;8(2):105–16. Gryseels B, Mbaye A, De Vlas SJ, et al. Are poor responses to praziquantel for the treatment of Schistosoma mansoni infections in Senegal due to resistance? An overview of the evidence. Tropical Medicine and International Health 2001;6(11):864–73. Ismail M, Botros S, Metwally A, et al. Resistance to praziquantel: direct evidence from Schistosoma mansoni isolated from Egyptian villagers. Am J Trop Med Hyg 1999;60(6): 932–5. King CH, Muchiri EM, Ouma JH. Evidence against rapid emergence of praziquantel resistance in Schistosoma haematobium, Kenya. Emerging Infectious Diseases 2000;6(6):585– 94. WHO. Report of the WHO Informal Con­ sultation on the use of praziquantel during pregnancy and albendazole/mebendazole in children under 24 months. WHO/CDC/CPE/ PVC/2002.4. Geneva: WHO; 2003. Ndibazza J, Muhangi L, Akishule D, et al. Effects of deworming during pregnancy on maternal and perinatal outcomes in Entebbe, Uganda: a randomized controlled trial. Clin Infect Dis 2010;50(4):531–40. Foster R, Cheetham BL. Studies with the schistosomicide oxamniquine (UK-4271). I. Activity in rodents and in vitro. Trans R Soc Trop Med Hyg 1973;67(5):674–84. Foster R, Cheetham BL, King DF. Studies with the schistosomicide oxamniquine (UK-4271). II. Activity in primates. Trans R Soc Trop Med Hyg 1973;67(5):685–93. WHO. Model List of Essential Medicines. Geneva: WHO; 2011.

247. Bassily S, Farid Z, Higashi GI, et al. Treatment of complicated schistosomiasis mansoni with oxamniquine. Am J Trop Med Hyg 1978;27 (6):1284–6. 248. Farid Z, Bassily S, Higashi GI, et al. Further experience on the use of oxamniquine in the treatment of advanced intestinal schistosomiasis. Ann Trop Med Parasitol 1979;73(5): 501–2. 249. Abaza HH, Hammouda N, Rabbo HA, et al. Chemotherapy of schistosomal colonic polyposis with oxamniquine. Trans R Soc Trop Med Hyg 1978;72(6):602–4. 250. Machado PA. The Brazilian program for schistosomiasis control, 1975–1979. Am J Trop Med Hyg 1982;31(1):76–86. 251. Stokvis H, Bauer AG, Stuiver PC, et al. Seizures associated with oxamniquine therapy. Am J Trop Med Hyg 1986;35(2):330–1. 252. Stokvis H, Bauer AG, Stuiver PC, et al. Convulsions after oxamniquine. Trans R Soc Trop Med Hyg 1987;81(5):880. 253. Doenhoff MJ, Kusel JR, Coles GC, et al. Resistance of Schistosoma mansoni to praziquantel: is there a problem? Trans R Soc Trop Med Hyg 2002;96(5):465–9. 254. Danso-Appiah A, De Vlas SJ. Interpreting low praziquantel cure rates of Schistosoma mansoni infections in Senegal. Trends Parasitol 2002; 18(3):125–9. 255. Liang YS, Coles GC, Doenhoff MJ. Detection of praziquantel resistance in schistosomes. Trop Med Int Health 2000;5(1):72. 256. Katz N, Rocha RS, de Souza CP, et al. Efficacy of alternating therapy with oxamniquine and praziquantel to treat Schistosoma mansoni in children following failure of first treatment. Am J Trop Med Hyg 1991;44(5):509–12. 257. Xiao SH, You JQ, Yang YQ, et al. Experimental studies on early treatment of schistosomal infection with artemether. Southeast Asian J Trop Med Public Health 1995;26(2):306–18. 258. Xiao SH, You JQ, Mei JY, et al. Preventive effect of artemether in rabbits infected with Schistosoma japonicum cercariae. Zhongguo Yao Li Xue Bao 1998;19(1):63–6. 259. Xiao SH. Development of antischistosomal drugs in China, with particular consideration to praziquantel and the artemisinins. Acta Trop 2005;96(2–3):153–67. 260. Utzinger J, N’Goran EK, N’Dri A, et al. Oral artemether for prevention of Schistosoma mansoni infection: randomised controlled trial. Lancet 2000;355(9212):1320–5. 261. Xiao SH, Booth M, Tanner M. The prophylactic effects of artemether against Schistosoma japonicum infections. Parasitol Today 2000;16 (3):122–6. 262. Mansour MM, Ali PO, Farid Z, et al. Serological differentiation of acute and chronic schistosomiasis mansoni by antibody responses to keyhole limpet hemocyanin. Am J Trop Med Hyg 1989;41(3):338–44. 263. Ferrari TC, Moreira PR, Cunha AS. Clinical characterization of neuroschistosomiasis due to Schistosoma mansoni and its treatment. Acta Trop 2008;108(2–3):89–97. 264. Watt G, Adapon B, Long GW, et al. Praziquantel in treatment of cerebral schistosomiasis. Lancet 1986;2(8506):529–32. 265. Ferrari TC. A laboratory test for the diagnosis of neuroschistosomiasis. Neurol Res 2010;32 (3):252–62. 266. Ong EL, Ellis ME. Acute schistosomiasis (Katayama fever): corticosteroid as adjunct therapy. Scand J Infect Dis 1989;21(4):473–4.

725.e6 SECTION 10 

Helminthic Infections

267. Harries AD, Cook GC. Acute schistosomiasis (Katayama fever): clinical deterioration after chemotherapy. J Infect 1987;14(2):159–61. 268. Ezzat FA, Abu-Elmagd KM, Aly MA, et al. Selective shunt versus nonshunt surgery for management of both schistosomal and nonschistosomal variceal bleeders. Ann Surg 1990;212(1):97–108. 269. Lebrec D, Poynard T, Hillon P, et al. Propranolol for prevention of recurrent gastrointestinal bleeding in patients with cirrhosis: a controlled study. N Engl J Med 1981;305(23):1371–4. 270. da Silva LC, Strauss E, Gayotto LC, et al. A randomized trial for the study of the elective surgical treatment of portal hypertension in mansonic schistosomiasis. Ann Surg 1986;204 (2):148–53. 271. Kurtis JD, Friedman JF, Leenstra T, et al. Pubertal development predicts resistance to infection and reinfection with Schistosoma japonicum. Clin Infect Dis 2006;42(12):1692–8. 272. Mkoji GM, Hofkin BV, Kuris AM, et al. Impact of the crayfish Procambarus clarkii on

273. 274. 275.

276. 277. 278.

Schistosoma haematobium transmission in Kenya. Am J Trop Med Hyg 1999;61(5):751–9. Jordan P. Schistosomiasis: The St. Lucia Project. Cambridge: Cambridge University Press; 1985. Hotez PJ, Molyneux DH, Fenwick A, et al. Control of neglected tropical diseases. N Engl J Med 2007;357(10):1018–27. Richards FO, Jr., Eigege A, Miri ES, et al. Integration of mass drug administration programmes in Nigeria: The challenge of schistosomiasis. Bull World Health Organ 2006;84 (8):673–6. Canning D. Priority setting and the ‘neglected’ tropical diseases. Trans R Soc Trop Med Hyg 2006;100(6):499–504. Fenwick A. New initiatives against Africa’s worms. Trans R Soc Trop Med Hyg 2006;100 (3):200–7. Fenwick A, Webster JP, Bosque-Oliva E, et al. The Schistosomiasis Control Initiative (SCI): rationale, development and implementation from 2002–2008. Parasitology 2009;136(13): 1719–30.

279. Hisakane N, Kirinoki M, Chigusa Y, et al. The evaluation of control measures against Schistosoma mekongi in Cambodia by a mathematical model. Parasitol Int 2008;57(3):379–85. 280. McCullough FS, Gayral P, Duncan J, et al. Molluscicides in schistosomiasis control. Bull World Health Organ 1980;58(5):681–9. 281. McManus DP, Loukas A. Current status of vaccines for schistosomiasis. Clin Microbiol Rev 2008;21(1):225–42. 282. Bergquist NR. Schistosomiasis vaccine development: approaches and prospects. Mem Inst Oswaldo Cruz 1995;90(2):221–7. 283. Bergquist NR, Colley DG. Schistosomiasis vaccine: research to development. Parasitol Today 1998;14(3):99–104. 284. Gryseels B. Schistosomiasis vaccines: a devils’ advocate view. Parasitol Today 2000;16(2): 46–8. 285. Hotez PJ, Bethony JM, Diemert DJ, et al. Developing vaccines to combat hookworm infection and intestinal schistosomiasis. Nat Rev Microbiology 2010;8:814–26.