Schistosomiasis then and now; what has changed in the last 100 years?
Centennial Reflections – a distinguished parasitologist reflects on a paper published in their field in Parasitology 100 years ago
A paper entitled “Bilharziasis in Natal”, published in Parasitology in 1918 by Dr F. G. Cawston, provides a window on the state of knowledge at the time (Cawston, 1918). He was a British physician and zoologist practising in South Africa, whose interest was aroused by a patient with “bilharziosis” (most probably infected with Schistosoma haematobium) (Cawston, 1915). In fact, the very first volume of Parasitology had published an article on the same topic (Turner, 1909), with speculations on the mode of transmission, but no mention of snails. Dr Cawston was of the opinion, echoing both Turner and Sir Patrick Manson in a lecture given in 1914, that the disease was caught by swimming in freshwater pools, an activity more common in boys than girls. Theodor Bilharz had identified parasitic trematodes as the cause of this disease, in Egypt in 1851, hence the term bilharziasis. However, the intestinal and urinary forms were not distinguished with any clarity. The disease had been recorded from South Africa as far back as 1864, associated with symptoms of haematuria and dystentery! Dr Cawston’s publication came at the trailing edge of a period of very intense research and to appreciate its context and significance we need trace the developments that preceded its publication.
Trematode cercariae emerging from molluscs were reported as far back as the 18th century and classified by taxonomists with the generic name Cercaria and suitable specific names. There was a vague realisation that these cercariae might be the larval stages of the numerous species of trematodes parasitic in vertebrates but the practical problem was making the link between mollusc and vertebrate. We know with hindsight that trematodes can have quite stringent species-specificity for their hosts. Over the winter of 1879/80 there was a massive mortality of sheep in the UK due to liver fluke infection. This outbreak prompted the Royal Agricultural Society of England to fund Algernon Thomas, working at the Oxford Museum, to investigate the causes. Rudolf Leuckart in Leipzig, Germany was also tackling the question of whether a snail might be the intermediate host of Fasciola. In 1880 the idea that snails might transmit disease was anathema to some people, occasioning correspondence in The Times newspaper disputing the existence of any such intermediate host. Thomas (1883) settled the question, describing the miracidium infecting the snail Lymnaea (=Galba) truncatula, the intramolluscan stages, and the metacercarial cyst on grass. The infection of livestock by ingestion of metacercaria via the oral route had a rather unhelpful influence on thinking about schistosomes.
Research on schistosomes progressed slowly after Bilharz’s initial description. In 1893 Patrick Manson finally separated the two clinical forms with lateral- and terminal-spined eggs (Leiper, 1915), and a new species, Schistosoma mansoni, was erected by Sambon in 1909 for the lateral spined egg producer (Leiper, 1915). In spite of Thomas’s publication, in 1884 Looss promoted the hypothesis that schistosome infection was direct, with miracidia hatching from eggs and penetrating the skin when humans entered water (Leiper, 2015). Unsurprisingly, attempts to infect potential mammalian hosts using miracidia failed, but 25 years later Looss was still advocating human skin penetration by miracidia (Looss, 1909). (Ironically, he was an associate of Leuckart in Leipzig where the life cycle of Fasciola was well understood.) Such was the confusion that in 1914 Manson himself hedged his bets by suggesting that miracidia might enter a mollusc, crustacean or arthropod, and encyst, before oral ingestion and entry into human tissues across the gut wall (c.f. Fasciola again) (Leiper, 1915). One beneficial outcome of this focus on schistosome transmission by an aquatic larva was the recommendation that urination and defaecation should not take place near water.
Independent of work in Europe, Japanese researchers were investigating six very focal diseases associated with rice paddies and nearby river banks (summarised by Tanaka & Tsuji,1997). Initially, the cause was thought to be ingestion of a poison but parasite eggs were observed in human livers at autopsy and in 1904 Katsurada described adult worms from a cat, with the same eggs in utero. Realising the similarity with S. haematobium he proposed the name Schistosoma japonicum for the new species (Katsurada, 1904). It was felt that since worms were found in mesenteric vessels, infection was likely via the oral route, with penetration of the gut wall (c.f. Fasciola again). However, Miyagawa (1912) immersed dogs and rabbits in paddy field water and showed they became infected with schistosomes. He also performed histology on exposed skin and demonstrated the presence of schistosomula. Finally the direct link between schistosomes and snails was made when Miyairi & Suzuki (1913) identified the snail Oncomelania in the paddy fields and showed that the emerging cercariae were the infective stage for mammals.
News of these rapid advances reached London and prompted the Wandsworth Expedition to the Far East (China and Japan), to investigate trematode diseases of humans. It was led by Professor Leiper of the London School of Hygiene and Tropical Medicine from February to August 1914 (Leiper & Anderson, 2015). The authors mention finding a small opeculate snail in Katayama, Japan (of Katayama Fever fame), now known as Oncomelania hupensis nosophora. In Shanghai these snails proved attractive to Schistosoma japonicum miracidia hatched from eggs shed by a heavily infected dog. Ultimately, a single mouse infected with cercariae teased from Oncomelania snails yielded paired adult worms in the mesenteric veins. The findings of Miyairi and Suzuki were confirmed.
In August 1914 the First World War began and in 1915 the British Government sent a mission, headed by Leiper, to Egypt where British troops were stationed. Its task was to obtain “a clear appreciation of the factors and the conditions under which the disease (i.e. schistosomiasis) was contracted and propagated” (Leiper, 1915). In the Introduction to his report on the mission he was very critical of Looss whose direct infection theory had dominated all research on schistosomes in Africa for the previous 25 years. Apparently Looss even objected to the description of S. haematobium and S. mansoni as two distinct species (Leiper, 2015).
Armed with his knowledge from Japan and China, Leiper’s plan was to collect and dissect large numbers of snails from districts near Cairo where schistosome infections were common. He knew that he was looking for a fork-tailed cercaria lacking a pharynx, and wanted to see if these could infect animals brought from the UK. He focused on El Marg village, with a S. haematobium prevalence of 91% in boys. He collected Planorbis boissyi (=Biomphalaria sp) Melania tuberculata and a Bulinus species. His problems were compounded by the observation of four trematode species with fork-tailed cercariae, namely “both forms” of S. haematobium (i.e. S. mansoni as well), S. bovis and Bilharziella polonica. He infected rats, mice and other species, and concluded that infection was by skin penetration (or drinking cercarial-contaminated water). He also recorded that the worms took 6-7 weeks to develop after exposure of monkeys. What is notable in this and all preceding work was the total focus on S. haematobium to the almost complete exclusion of S. mansoni. Was it simply that haematuria and eggs in the urine were very visible manifestations, compared with eggs in faeces? Leiper subsequently published a note stating that Bulinus contortus (= B. truncatus) and B. dybowski (unknown) shed cercariae that gave rise to worms releasing terminal spined eggs whilst cercariae from Planorbis boissyi (=Biomphalaria species) gave rise to worms laying lateral spined eggs (Leiper, 1916).
This brings us back to Cawston’s 1918 paper. He was aware of the discoveries about the life cycle of S. japonicum and the results of the Wandsworth expedition. To investigate schistosome transmission in South Africa, in 2015 he first attempted to infect the abundant Lymnaea natalensis snails using S. haematobium miracidia without success (ironically these snails are hosts of Fasciola gigantica). In 1916 he collected large numbers of Physopsis africana (= Bulinus africanus) from various parts of Natal. He described specimens shedding fork-tailed cercariae, and containing sporocysts. He subsequently made a study of the freshwater snails of Natal, noting additionally Planorbis (=Biomphalaria) pfeifferi but saying that Schistosoma mansoni was absent. (Today it is listed as endemic to KwaZulu-Natal, along with S. mattheei in livestock.) He also collected Isidora tropica and Isidora forskali (=Bulinus tropicus and B. forskali) which did not shed fork-tailed cercariae but are known schistosome hosts elsewhere. He was successful in infecting Bulinus africanus with miracidia of S. haematobium and obtaining cercariae but he failed to infect rats, guinea pigs and pigeons with these.
Cawston also took the standpoint of the medical practioner, noting that in one school 76% of boys were infected and he lists symptoms such as renal calcium deposits, renal colic and haematuria. He did not consider the infection life-threatening or even life-shortening. His advice was to avoid bathing in freshwater pools and his list of treatments intended to relieve symptoms rather than cure patients, included diuretics and urinary antiseptics, such as Hexamine, Aspirin, the local herbal medicine Buchu, and tincture of henbane (Hyoscamus)!
What is the situation 100 years after the publication of Cawston’s paper? Well we now have a much greater understanding of the impact of the disease, and an appreciation that high worm burdens generate severe and life-threatening pathologies. The application of the disability-adjusted life year (DALY) has provided a rational method to assess disease impact (King et al., 2005) and one achievement of treatment programmes has been to reduce overall worm burdens and hence morbidity. It took a long time for therapies to emerge that would actually eliminate the adult worm populations from infected individuals, with early attempts relying on toxic compounds like antimony potassium tartrate (Cioli et al., 1995). The introduction of modern chemotherapeutics dates to the 1960s and 1970s but compounds like Hycanthone and Amoscanate provide a salutary warning. The first proved to be highly mutagenic while the second caused liver toxicity, and both compounds were withdrawn. The principal survivor is Praziquantel, active against adult worms of all schistosome species (and tapeworms). It now underpins programmes aimed at controlling and ultimately eradicating the disease, although it does have some limitations such as inactivity against schistosomula.
The number of schistosome species known to infect humans now stands at six, with description in the intervening period of S. intercalatum and S. guineensis in Central Africa, and of S. mekongi is South-East Asia. However, the advent of molecular genetics has revealed a more complex situation with the discovery of hybrids between human and animal schistosomes (Webster et al., 2013). The hybridisation appears to be introgressive and may have an impact on the adaptation and evolution of the parasites. Indeed, a new focus of schistosome infection in humans was identified in Corsica in 2013, where Bulinus truncatus is endemic (Boissier et al., 2013). Molecular analysis showed that hybrids between S. haematobium and S. bovis were present, very likely originating in Senegal. Given the abundance of the snail host, the fear is that the hybrid could become established in rodents or livestock as reservoir hosts.
Before the molecular era, the classification of the snail intermediate hosts relied primarily on shell characteristics, a particularly plastic feature (Mandahl-Barth, 1965). The physiological basis for the compatibility between particular schistosome and snail species remains something of a mystery. However a better definition of the snail hosts is being achieved. The thirty six species within the Genus Bulinus, hosts of several schistosome species, have been placed into four species groups by DNA barcoding but substantial genetic diversity has been revealed within groups and individual species (Kane et al., 2008). The same approach has been used with the Genus Biomphalaria, the hosts of S. mansoni around the world (Zhang et al., 2017).
Yet not all is rosy. We have a better understanding of how adult worms can live in the bloodstream for decades yet survive immune attack (Wilson and Coulson, 2009; Skelly and Wilson, 2006). A vaccine would be a great addition to the toolbox of control measures, but progress has been painfully slow. Only Bilhvax against S. haematobium has undergone Phase III trials in humans but failed to elicit significant protection in Senegalese recipients (Riveau et al. 2018). Other candidates are in human trials and results are eagerly awaited (Hotez et al., 2016). Currently, diagnosis presents a significant problem. The detection of S. haematobium eggs in urine was always a relatively simple matter, although its sensitivity relative to actual worm burden is unknown, due to the inaccessibility of the adult worm population in the venous vesical plexus, and the absence of a large animal model where that parameter might be established. The introduction of the standardised Kato/Katz faecal smear test (Katz et al., 1972) did much to improve diagnosis of S. mansoni and S. japonicum infections but is of low sensitivity (Wilson et al., 2006). The emphasis has shifted to the detection of schistosome antigens in the bloodstream and urine, especially using dipstick assays (Corstjens et al., 2014). This has led to the realisation that there is much more low-intensity schistosomiasis than previously thought (Colley et al., 2017). The goal of routine detection of a single worm pair has yet to be reached (Ogongo et al, 2018) but is crucial if eradication of the disease is to be achieved.
Boissier J, Grech-Angelini S, Webster BL, Allienne JF, Huyse T, Mas-Coma S, Toulza E, Barré-Cardi H, Rollinson D, Kincaid-Smith J, Oleaga A, Galinier R, Foata J, Rognon A, Berry A, Mouahid G, Henneron R, Moné H, Noel H, and Mitta G. (2016) Outbreak of urogenital schistosomiasis in Corsica (France): an epidemiological case study. Lancet Infectious Diseases 16 (8) 971-979.
Cawston FG (1915) Bilharziosis in Natal. British Medical Journal 2864, 20 November, 746.
Cawston FG (1918) Bilharziasis in Natal. Parasitology 11, 83-93
Cioli D, Pica-Mattoccia L, and Archer S. (1995) Antischistosomal drugs: past, present … and future? Pharmacology & Therapeutics 68, 35-85.
Colley DG, Andros TS and Campbell Jr CH (2017) Schistosomiasis is more prevalent than previously thought: what does it mean for public health goals, policies, strategies, guidelines and intervention programs? Infectious Diseases of Poverty 6, 63.
Corstjens PL, De Dood CJ, Kornelis D, Fat EM, Wilson RA, Kariuki TM, Nyakundi RK, LoVerde PT, Abrams WR, Tanke HJ, Van Lieshout L, Deelder AM and Van Dam GJ (2014) Tools for diagnosis, monitoring and screening of Schistosoma infections utilizing lateral-flow based assays and upconverting phosphor labels. Parasitology 141, 1841–1855.
Hotez PJ, Bottazzi ME and Strych U (2016) New Vaccines for the World’s Poorest People. Annual Review of Medicine 67, 405-17.
Kane RA, Stothard JR, Emery AM, and Rollinson, D (2008) Molecular characterization of freshwater snails in the genus Bulinus: a role for barcodes? Parasites & Vectors, 1, 15
Katsurada F. 1904. Determination of the cause of a new parasite disease seen in Yamanashi and other prefectures. Tokyo rji Shinshi 1371: 13-32 (in Japanese).
Katz N, Chaves A and Pellegrino J (1972) A simple device for quantitative stool thick-smear technique in Schistosomiasis mansoni. Revista do Instituto de Medicina Tropical de São Paulo 14(6):397-400
King CH, Dickman K, and Tisch DJ (2005) Reassessment of the cost of chronic helmintic infection: a meta-analysis of disability-related outcomes in endemic schistosomiasis. Lancet 365, 1561–1569
Leiper RT (1915) Report on the results of the Bilharzia mission in Egypt, 1915. Journal of the Royal Army Medical Corps 25 (July), 1-48.
Leiper RT (1916) On the relation between the terminal-spined and lateral-spined eggs of bilharzia. British Medical Journal 2881, 18 March, 411.
Leiper RT and Anderson EL (1915) Observations on the spread of Asiatic schistosomiasis. British Medical Journal 2822, 30 January, 201.
Looss A (1909) Bilharziosis of women and girls in Egypt in the light of the ‘skin infection theory’ British Medical Journal 2517, 27 March, 773-777.
Mandahl-Barth, G (1965) The species of the Genus Bulinus, intermediate hosts of Schistosoma. Bulletin of the World Health Organisation 33, 33-44.
Miyagawa Y (1912) Route of migration of Schistosoma japonicum from the skin to the portal vein, and morphology of the young worm at the time of penetrating the skin. Tokyo Medical Journal 26: 3-4 (in Japanese).
Miyairi K and Suzuki M (1913) On the development of Schistosoma japonicum. Tokyo Iji Shinshi 1836, 1961-1965 (in Japanese).
Ogongo P, Kariuki TM and Wilson RA (2018) Diagnosis of schistosomiasis mansoni: an evaluation of existing methods and research towards single worm pair detection. Parasitology 145,1355-1366.
Riveau G, Schacht AM, Dompnier JP, Deplanque D, Seck M, Waucquier N, et al. (2018) Safety and efficacy of the rSh28GST urinary schistosomiasis vaccine: A phase 3 randomized, controlled trial in Senegalese children. Plos Neglected Tropical Diseases 12, e0006968.
Skelly PJ and Wilson RA (2006) Making sense of the schistosome surface. Advances in Parasitology 63,185-284.
Tanaka H and Tsuji M (1997) From discovery to eradication of schistosomiasis in Japan: 1847-1996. International Journal for Parasitology 27 (12) 1465-80
Thomas AP (1883) The life history of the liver fluke (Fasciola hepatica). Quarterly Journal of Microscopical Science 23, 90-133.
Turner GA (1909) Bilharziosis in South Africa. Parasitology 1, 195-217.
Webster BL, Diaw OT, Seye MM, and Webster JP, Rollinson D. (2013) Introgressive hybridization of Schistosoma haematobium group species in Senegal: species barrier break down between ruminant and human schistosomes. Plos Neglected Tropical Diseases 7 (4) e2110
Wilson RA and Coulson PS (2009) Immune effector mechanisms against schistosomiasis: looking for a chink in the parasite’s armour. Trends in Parasitology 25, 423-31.
Wilson RA, van Dam GJ, Kariuki TM, Farah IO, Deelder AM and Coulson PS (2006) The detection limits for estimates of infection intensity in schistosomiasis mansoni established by a study in nonhuman primates. International Journal for Parasitology 36, 1241–1244.
Zhang SM,, Bu L, Laidemitt MR, Lu L, Mutuku MW, Mkoji GM and Loker ES (2018) Complete mitochondrial and rDNA complex sequences of important vector species of Biomphalaria, obligatory hosts of the human-infecting blood fluke, Schistosoma mansoni. Scientific Reports 8, 7341
Schistosoma haematobium egg, image public domain.
Bulinus africanus [CC-BY-NC-SA] Source: https://www.inaturalist.org/photos/34258957