Early Schistosomiasis Studies
This page is designed to show the early stages of schistosomiasis research. It will also refer to some of the publications that the first workers in this field produced, introducing some of the key players in the early study of this disease.
• The 'Prehistory' of Schistosomiasis
Schistosomiasis, or as it is more commonly known, bilharzia is a infection caused by a trematode helminth. This causative agent has however only relatively recently been identified, but the symptoms of the disease have been recognised for a very long time.
Schistosome eggs have been recovered from both Chinese and Egyptian mummies, showing that the infection was present in both of these early civilisations of mankind. This was first noted as early as 1910 by Sir Armand Ruffer, who found calcified eggs in the kidneys of two mummies of the twentieth dynasty.
This is further illustrated by the identification of hieroglyphics in the "Papyrus Ebers" which appear to refer to the disease, bloody urine (a typical symptom of infection with Schistosoma haematobium) being frequently mentioned. Here this disease was mentioned by name, it's hieroglyphic being a dripping penis. Elsewhere in the Middle East ancient Assyrian records also have reference to this disease which gave rise to bloody urine. Showing knowledge of the disease was widespread even in ancient times.
In the Far East infection with the related species Schistosoma japonicum was also recognised, where it was known as 'Katayama' disease, characterised by enlargement of the liver and spleen, abnormal feelings of hunger, bloody diarrhoea and occasionally fever (the so called 'Katayama Fever'), a characteristic of infection with this parasite.
The causative agent of these diseases was however not known until the middle of the 19th century.
• The Discovery of the Schistosome Parasite
Schistosomiasis in man was first described by Theodor Bilharz in 1851, working at the Kasr-el-Aini hospital in Cairo. In a letter to Prof. Th. von Siebold he describes his new discovery during a post-mortem examination thus;
"After my attention had been drawn to the liver, I soon found a white long helminth in the blood of the portal vein in quantity, which I assumed to be a nematode but which I immediately recognised as something new. The microscope revealed a splendid distomum with a flat body and a curving tail which exceeded the body about ten times in length. Yet the tail was not loosely inserted like those of the cercariae but was the continued flat substance of the body of the worm itself which was rolled at the side against the abdominal surface to a half-channel."Theodore Maximillian Bilharz
1825 - 1862
He soon realised that these helminths were trematodes, with uniquely two sexes, the flattened worms he had first seen being the males which held a single threadlike female in a fold of its body (the gynaecophoric canal), as described in a letter a few months later;
"I have not told you yet about the new phases into which my worm of the portal vein has entered. This has not developed into a fairy tale, as I had assumed, but something more miraculous -- a trematode, with separate sexes. The worm which I had described to you in my last letter was the male. When I examined the intestinal veins more carefully... ... , I soon found samples of the worm which harboured a grey thread in the canal of their tails. You can picture my surprise when I saw that a trematode projected out of the anterior opening of the canal"
He then went on to describe the morphological features of this second threadlike worm, which on the basis of internal structures such as the vitellaria and ovaries, he correctly identified as the female parasite, which he named Distomum haematobium.
The next year he described some further findings, based on more post-mortem examinations;
"Opening the urinary bladder we detected many excrescence's which are unfamiliar in Europe. .... I cut into the largest of these excrescence's and found a white thread remaining on the knife. I looked at it more closely and discovered our Distomum haematobium."
He then went on to describe the females, which he noted looked different from those he had previously seen, (they;
"...differed from those found in the intestinal veins by the greater clarity of their inner organs... ... and even more so by the immense abundance of ova, which were present in all stages of development"
However, even with these differences, he still thought he was dealing with a single species. He also described the eggs associated with these parasites as having;
"...a thin, delicate eggshell with a pointed process"
In a subsequent paper in the same journal he went on to described the examination of eggs removed from the parenchyma of the bladder, and observed them hatching to release a small active embryo (the miracidium). In further descriptions from post mortem autopsies he noted ova present in the liver, and described them thus;
"...I saw strange leguminous bodies equipped with indented excrescence's which were located at the points of calcification of the liver next to the ova of Distomum haematobium. ... ...They appeared to me as brownish yellow, oblong bodies which were blunt on both ends. On one side, drawn nearer to the blunter end, there was a conical process, slantingly directed towards the more pointed end"
These were in fact the eggs of a unsuspected different species (later to be identified as Schistosoma mansoni. He was puzzled by these bodies, and went on to speculate;
"What are these bodies? Are they a second form of ova or a kind of cocoon which the animal retains after creeping out of the ovum? It seems to me without any doubt that these capsules belong to the stages of development of our Distomum haematobium and not to another being since I had found them mixed with the unquestionable ova of the Distomum haematobium not only in the points of calcification of the liver but in the submucosa and mucosa of the colon along with acute dysentery. I also found them--if only once, but without any doubt--in the oviduct of a female worm whose further course contained the usual ova. I admit that for the time being no sure interpretation of the mentioned capsules is possible from the present facts. It may be assumed, however, that they are a cover with which the delicate embryos--having come from the genuine ova of the Distomum haematobium--cover themselves in order to leave the human body."
Unfortunately the identification of both types of egg in the lesions, and more importantly both types of egg within a single female must have been a mistake, as it is now known that they are derived from two distinct species. This mis-identification to some extent held up further research into the biology of these parasites in Egypt, in particular the identification of their lifecycle. It also led to other mis-classifications. For example a new species Bilharzia capensis in South Africa was described by J. Harley in 1864 on the basis that this species did not produce these lateral spined objects, along with some prescient speculations on the further, as yet unknown, lifecycle of the parasite;
"It may be safely assumed that between the ciliated embryo already described and the adult sexual animal, there are probably two other distinct forms, which serve to complete the chain of metamorphoses connecting these two extremes of development. Fresh water mollusca and fish are probably the victims selected by the parasite during its development through these intermediate stages".
• The Japanese Connection - The discovery of a second species of schistosome
Concurrently with the work carried out by Bilharz in Egypt, other Scientists and Physicians were also becoming aware of this disease, particularly in Japan. In 1847, four years before Bilharz described his new trematode, Yoshinao Fujii a Physician working in Numakuma County, reported a disease he had noted in the district of Kawanami thus;
"During the past 2 or 3 years, farmers have had small eruptions on their legs when they entered the water to cultivate the rice fields. The eruptions are unendurably painful and itchy. Cows and horses also show the same symptoms. Most of the residents suffer from this disease, and they consider that the symptoms are due to the lacquer spread out in this area in ancient times".
He went on to describe the symptoms of the disease in detail, illustrating all the important features of this disease, including the frequent death of the patients and lamenting the fact that there did not appear to be any cure for it. He also makes the further observation that the disease was also found in cows and horses, many of which were also killed by the disease. This 'zoonotic' aspect to the infection is now known to be an important feature of the causative agent of this disease,Schistosoma japonicum. He also noted that the disease was most severe in Katayama district, but was also found in several other nearby areas, notably Ikariyama district, and that it was called Katayama disease. The real cause of the disease was not known to him, but he thought it might be a poison, although he did not believe the legendary story of the lacquer, further, noting optimistically;
"Recently, medicine has made much process. Techniques and instruments have become excellent. I hear that methods of analysis have been developed in Western countries. If we could analyse the mud, we should be able to make clear what the poison is. If we could know the causative agent we should be able to cure the disease. Then this stubborn disease, lasting for scores of years, would be cured instantly, just as ice melts. How happy the people would be! For that reason I describe the disease here again and hope all learned men throughout the country will quickly solve this problem."
It was not however until 1904 that the causative agent of this disease was discovered, almost simultaneously by two workers. In this year Fijiro Katsurada, Professor of Medicine at Okayama Medical School, was investigating Suishuchoman disease, (presenting symptoms simnilar to Katayama disease and now known to be identical) in patients from the Kofu region of Yamanashi province. Here he noted trematode eggs similar to those of Schistosoma haematobium in the faeces of five of his twelve patients. He therefore suspected that the disease was caused by a related parasite, although he had at that time no opportunity to post mortem examinations to find it. He noted however;
"Since I had previously ascertained that trematodes (e.g. P. westermani ) which most often invade humans are also not infrequently found in cats and dogs, I therefore believed that a trematode causing our disease could be found in these animals. I therefore autopsied two dogs and a cat, and in the latter I found a part of a male trematode. I later received a second cat from the province of Yamanashi and found in the portal vein as well as in its tributaries numerous trematodes which were in the exact form as that discovered in the first cat."
"In most cases the eggs are also found in the mucosa and submucosa of the intestine, primarily of the large intestine. The eposition of the eggs causes more or less serious inflammation which leads in part to tissue destruction, in part to tissue proliferation... ... they (the eggs) are carried by the blood stream and are deposited in practically all organs, though in fewer numbers. ...It is quite noteworthy that so far bladder problems brought about by our parasite have never been observed, while Schistosoma haematobium almost always causes them".
NB. Schistosoma japonicum has now been eradicated from Japan, the last cases being seen in 1978, but is a widespread infection in other parts of the Far East.
• The Discovery of the Parasite Schistosoma mansoni
Until 1906 then it was assumed that this new unusual trematode was represented by the two species, Schistosoma japonicum in the Far East, and the parasite originally described by Bilharz, Schistosoma (Distomum) haematobium in man in other tropical regions. Furthermore it was thought that this single species of Schistosoma haematobium was present in both the mesenteric veins and blood vessels around the bladder, and that this single species produced only terminally spined eggs. It had however been noted by Sir Patrick Manson, Physician to the Seamen's Hospital in Greenwich, that the eggs passed in the urine from schistosomiasis patients were all terminally spined, whilst only those found in the faeces had the lateral spine. He then went on to speculate;
"Possibly there are two species of Bilharzia, one with lateral spined ova depositing its eggs in the rectum only, the other haunting the rectum and bladder indifferently".
It was not until 1907 that this confusion was cleared up, when Luigi Sambon of the London School of Tropical Medicine described the parasite Schistosoma mansoni, named after Patrick Manson as the parasite responsible for the lateral spined eggs.
"...in appreciation of this, one of his many genial intuitions".
An entirely different species, keeping the name of Schistosoma haematobium , was shown to produce the terminal spined eggs. For a time this discovery caused much dispute, many distinguished researchers including Arthur Looss, at the time one of the most prominant helminthologists. The controversy over the discovery of S. mansoni lasted for a number of years, but was only finally laid to rest when the lifecycle of the parasite was finally determined.
• The Mode of Parasite Transmission Investigated
The stage now reverts to the Far East, and the study of Schistosoma japonicum in Japan. Until this point it was still not clear how the parasite was transmitted to man, although some of workers had made educated speculations based on the known lifecycles of other trematodes. For example Looss speculated that there was no intermediate host, and the miracidium was directly infective to man. On penetration of the skin he thought the miracidium made its way to the liver, where a larval sporocyst stage formed, which then directly grew into the adult parasite, and Katsurada, the discoverer of S. japonicum agreed with him. In contrast Manson correctly, by analogy with the lifecycle of Fasciola , (recently discovered in the 1880's by Algernon Thomas working in Britain) guessed that the miracidium passed into a snail intermediate host to produce infective cercariae. However he then thought that the disease was passed on to man orally, either by ingestion of cercariae directly in the drinking water, or by accidental ingestion of the intermediate host, (also see the work of J. Harley described above). None of these speculations however had any scientific basis, beyond the use of analogy with other parasites.
Then in 1909 Professor Kan Fujinami and Assistant Professor Hachitaro Nakamura of Kyoto University, working on Katayama (also locally called "kabure") disease in the Takaya River valley. The local people in the affected areas held that "kabure" occured after wading in muddy rice paddies, and people coming into the area from other districts also said that they attributed their "kabure" disease to working in rice paddies. To examine these beliefs they carried out a series of experiments using calves taken from disease free areas of Japan. The faeces of these animals were examined to show that they did not have prior infections, and were then divided into four groups;
Group A had their mouths covered, (to prevent possible ingestion of the parasites infective stages), and were made to stand either in the waters of the Takaya River, which, it was noted, received large volumes of water from the local rice paddies and irrigation canals, oractually in the waters of the rice paddies and irrigation canals.
Group B were allowed to drink the waters of the Takaya River and eat the local vegetation freely, but their skin was protected from water contact by waterproof leg bags.
Group C were given the same food as group A, but were not taken out of their barn, except for one calf that was briely exposed to the water of a local irrigation canal.
Group D were allowed to roam freely.
On later examination it was found that all the calves from Groups A and D were infected, whilst in those from Group B only one worm pair was found in one calf. It was further noted that those animals from Group A placed in the water of the Takaya river had far fewer parasites than those exposed to the waters of the paddy fields or irrigation canals. On examination of Group C, it was found that the animals kept in the barn all the time were free of parasites, whilst the animal exposed briefly to irrigation canal water had a high level of parasitaemia. The conclusions that they drew from this experiment were as follows;
"...The explanation for this appears to be simple; the source of the disease acumulates, no doubt, in large quantities in stagnant dirty water, as in irrigation canals, but the risk is relatively less in the flowing water of the Takaya River, especially when it is in flood. The great difference between the findings for Group A and B is obvious, like snow and charcoal, and we feel that the problem of the mode of entry of the infection, which has vexed scientists for so long, has at last been incontrovertibly solved. It is accepted that the mode of entry is normally the skin; what must now be ascertained is the number of days taken by the newly penetrated parasites (we are still not sure whether or not this is the miracidium mentioned by Mr Looss in connection with schistosomes in Egypt) to develop in the skin and further inside the bodily tissues".
Furthermore, discusing the single animal from Group C that was infected;
"...it was shown that infection is easily caused by bodily contact with water in a suitable place even for a short space of time and in a place supposed to be not particularly risky. This must also occur with humans and helps us to understand why a person arriving from another district for rice planting seems to contract "kabure" in a single morning".
• The Final Breakthrough - The Parasite's Lifecycle Discovered
The results of Fujinami and Nakamura therefore disproved Patrick Manson's hypothesis that infection was aquired orally, and appeared to show support for Looss's idea of a directly infective miracidium. The lifecycle of the parasite was still however a mystery, and many investigators were engaged in trying to dispell the controversy between Manson's and Looss's hypotheses.
Patrick Manson, at the London School of Tropical Medicine, proposed that an investigation of the oriental schistosome S. japonicum would be fruitful in the investigation of the parasites lifecycle, as it could be transmited experimentaly to animals. He then proposed that Robert Leiper, Wandsworth research scholar and lecturer in helminthology at the London School and E. L. Atkinson a surgeon in the royal navy, be sent to Shanghai, and it was this project that an Advisory Committe of the Tropical Disease Research Fund sent on a special comision to investigate the disease in 1913.
However it was work carried out by two Japanese investigators, Keinosuka Miyairi and his assistant Masatsuga Suzuki that for the first time elucidated the complete lifecycle of a species of schistosome.
The initial report of 1913 described how they had taken a piece of cow dung containing eggs of S. japonicum and mixed it with water to try a stimulate egg hatching. They noted how the miracidia withi the egg shells became activated, initially with the flame cells moving, followed by wriggling of the larval worm within the shell, and finally hatching as the egg shell broke lengthwise. They then went on to repeat these observations using human faeces containing eggs, noting that;
"Miracidia out of the shell were observed to move around most actively for the first 1 or 2 hours, following which they became less and less active. after 10 hours they were so weak that even if they encountered a suitable host they were unable to attack it".