Читать книгу The Power of Plagues - Irwin W. Sherman - Страница 26

A look back

The Assyrian and Babylonian literature, as well as the Egyptian papyrus from Kahun written in about 1900 B.C., describe a disease that causes blood to appear in the urine (hematuria). And near the Louvre Museum in Paris there is a stone from ancient Egypt that says, “Anyone who moves this boundary stone will be covered with bloody urine.” Hematuria was described by the father of Arabian medicine, Avicenna (930-1037), in his Canon of Medicine, but the condition, called a-a-a, was recognized much earlier and is mentioned in the Ebers papyrus, dated ~1500 B.C. and named after Georg Ebers, who in 1862 found the paper in a tomb in Thebes, Egypt. There is even a hieroglyphic sign showing a penis dripping fluid, and this too may be blood (Page 44). Such a sign was not considered to be connected with disease, but as a mark of puberty in the male child. Many remedies for this disease are described in the Ebers papyrus, suggesting that this condition was widespread. And in a relief of the tomb of Ptah-Hetep I and Mehou of the Sixth Dynasty at Sakarrah there are figures of fishermen and bargemen with enlarged abdomens—surely representing the pathology of chronic snail fever or blood fluke disease. In 1910, Marc Armand Ruffer examined several Egyptian mummies from the Twentieth Dynasty (1200-1000 B.C.) and found the calcified eggs of the blood fluke in the kidneys of several mummies (Fig. 3.2B). Fossil snails capable of transmitting blood fluke disease have been found in the well water of Jericho. It has been hypothesized that the water was infested with infected snails, resulting in a high level of disease. Too debilitated by disease to defend the city or repair the decaying walls, the people of Jericho were easily defeated by Joshua’s army. Joshua, though unaware of the cause of the disease that contributed to his success, but wanting to prevent its spread, destroyed Jericho and proclaimed a curse on anyone who would rebuild it. The city remained deserted for 500 years. Centuries of recurring drought destroyed the snails, and thus the city has remained free of disease to this day. All this suggests that snail fever has existed in tropical and subtropical parts of the world, but especially in Egypt, since ancient times.

Soon after humans settled down and food production began in the Fertile Crescent (~8000 B.C.), it spread to other parts of Eurasia and North Africa. The plants (as well as the domesticated animals) that formed the basis for agriculture in the valleys between the Tigris and Euphrates Rivers were also cultivated in the Nile Valley of Egypt, and this triggered the rise of Egyptian civilization. These same agricultural practices, though, sustained by the Nile, also sowed the seeds of Egypt’s decline.

The land of the pharaohs flourished for 27 centuries, and its accomplishments, even today, are truly impressive. When Herodotus, the Greek historian, made a tour of Egypt in 400 B.C., he wrote of “wonders more in number than those of any other land.” And he went on to say that “when the Nile inundates the land all of Egypt becomes a sea and only the towns remain above water. Anyone traveling from Naucratis to Memphis sails right alongside the pyramids, and when the waters recede they leave behind a layer of fertile silt—’black land’—the Egyptians call it, to distinguish it from the sterile ‘red land’ of the deserts. Egypt is the gift of the river.”

In some ways Nature favored Egypt because, unlike Mesopotamia, which stood on an open plain and was unprotected from marauding tribes, the deserts that bordered the Nile discouraged invasion, and so the people lived in relative security. The villages shared the river and merged into cities. To tap the bounty of the Nile required the cooperation and organization of the people, with social and political structures developing therefrom. All power was invested in the pharaohs, who were both kings and gods. Below the pharaoh was a vast bureaucracy that rested on the shoulders of the workers and the peasantry. Egypt’s people, however, who built enduring stone monuments for their pharaohs, were racked with a debilitating disease, snail fever. And although medical science began in Egypt, the doctors and surgeons could not keep this disease at bay. There is a reason for this: the early civilizations of Egypt and those of the Fertile Crescent (Sumer, Assyria, and Babylon) were based on agriculture, and this agriculture required irrigation and/or natural flooding by the rivers. Irrigation farming, especially in the tropics, created conditions favorable for the transmission of snail fever caused by the blood fluke. Blood fluke disease—the plague of the pharaohs—is not a fatal disease, as is malaria or yellow fever; it is, however, a corrosive disease. And although there may have been a time when the natural flooding of the Nile River made snail fever a seasonal problem, once there was irrigation it became a year-round problem, since infections could be acquired from the standing water in the irrigation channels. Consequently, as William McNeill wrote in his book Plagues and Peoples,

there was a listless and debilitated peasantry handicapped … for the … demanding task of resisting military attack or throwing off alien political domination and economic exploitation. Lassitude and chronic malaise … induced by parasitic infections was conducive to successful invasion by the only kind of large-bodied predators human beings have to fear: their own kind, armed and organized for war and political conquest.

McNeill also suggested that the rule of the pharaohs may have been due to the power of the snail and the blood fluke and malaria—the classic plagues of Egypt—which debilitated the populace.

And so it was that snail fever did its work. By 660 B.C., Egypt became subject to internal political dissension and to attack by their iron-armed neighbors (the Assyrians), and their civilization, based on agriculture and copper weapons, began to collapse. The Persians overran Egypt in 525 B.C. The cause of snail fever, the disease that set the Egyptian civilization on its inexorable downward spiral, was unknown to the ancient Egyptians because the transmission stages of the parasite (eggs, miracidia, and cercaria) are microscopic; in addition, the adult worms themselves are tiny and live within the small blood vessels, and so they were unnoticed for thousands of years.

Search for the destroyer

Blood fluke disease, also known as snail fever and endemic hematuria, involves feces or urine, water, snails, and a flatworm. The first Europeans to experience the disease on any scale appear to have been the soldiers of Napoleon’s army during the invasion of Egypt (1799-1801). The symptoms of the disease, bloody urine, were rife among the soldiers. Baron Jean Larey, a military surgeon, noted its high frequency in the men; he believed, however, that the excessive heat during the long marches was the cause. The connection between hematuria and a parasite did not occur until 1851. In that year Theodor Bilharz, a German physician working in Egypt, while carrying out an autopsy on a young man, made a startling discovery: worms were found in the blood vessels, a location never before encountered (Fig. 3.2E). He named the worm Distomum (meaning “two mouths”) haematobium (from the Greek words haema, meaning “blood,” and bios, meaning “to live in”). In 1858 the name was changed to Schistosoma (from the Greek words schisto, meaning “split,” and soma, meaning “body”). Today, blood fluke disease is called schistosomiasis or bilharzia, the latter in honor of Bilharz’s discovery. (During World War I, British soldiers found it easier to call the disease “Bill Harris.”)

In 1851, Bilharz reported that he had seen microscopic eggs with a pointed spine in the female worm (Fig. 3.2C), and in the following year he observed these eggs in the bladder; within the egg he observed a small, motile embryo. He also found that the eggs would hatch to release a small ciliated larva (Fig. 3.2F) that swam around for about an hour and then disintegrated. This work was confirmed in 1863 when John Harley, a London physician, examined a patient with hematuria who had previously lived in the Cape of Good Hope in South Africa. Examining the blood-tinged urine in a drop of water under the microscope, he found schistosome eggs, and several of these hatched to give progeny that swam by using their cilia (Fig. 3.2G). But there remained a puzzle: how was the infection transmitted? Bilharz and others were aware that flukes closely related to Schistosoma had intermediate stages in snails, but when Harley examined snails from a region where schistosomiasis was prevalent, he found no evidence of larval stages. Despite this failure, the suspicion remained that humans acquired the infection either by eating infected snails or by drinking water containing the ciliated larva called miracidia. In 1870, Spencer Cobbold, working in London, obtained eggs from a young girl living in the Cape of Good Hope and found that although the eggs would not hatch in urine, they did so in fresh or brackish water. Then, in about 1904, Japanese physicians found that a related blood fluke, named Schistosoma japonicum, could also infect humans, but this species had eggs without a spine. In 1905, Patrick Manson discovered another type of schistosome egg, one with a spine on its side (Fig. 3.2D); this was in the feces of an Englishman who had lived in the West Indies but had never visited Africa; this new type was duly named Schistosoma mansoni. Now there were three known species of human-infecting blood flukes.

The life cycle and mode of transmission of the schistosome to a human were first demonstrated between 1908 and 1910 in Japan. Fujinama and Nakamura found that when the tails of mice were immersed in water from rice fields known to have a high incidence of bilharzia, they became infected with S. japonicum. Shortly thereafter it was possible to show that the miracidia were able to penetrate freshwater snails in the rice paddies, and Ogata found that a tailed larva (called a cercaria) emerged from infected snails and could directly penetrate the skin of mice (Fig. 3.2G). This suggested that species other than S. japonicum might have a similar life cycle. At the outbreak of World War I the British became concerned about the potential deleterious effects of schistosomiasis on their troops in Egypt. In 1915 the British War Office sent Robert Leiper to Cairo “to investigate bilharzia … and advise as to preventive measures to be adopted.” Leiper collected freshwater snails, identified them, and determined whether they were infected, either by allowing the snails to release cercaria or by dissecting the snails to find other larval stages (called sporocysts). Within weeks he and his team identified the snails Bulinus and Biomphalaria as the vectors. (Because the snail vector is critical to transmission, schistosomiasis is called “snail fever.”) Leiper went on to show, by placing the tails of the mice in cercaria-infested water, that the skin of mice could be directly invaded by the cercaria. This suggested that the infection was acquired by bathing in infested water. But could the infection also be acquired by ingestion? Because Leiper was able to show that when cercaria were placed in dilute hydrochloric acid (similar in concentration to that found in the human stomach) they were killed, this route of infection seemed most unlikely. Leiper was also able to show that the adult S. mansoni and S. haematobium were different from one another and that cercaria hatched from Biomphalaria produced eggs with lateral spines whereas those from Bulinus produced eggs with a terminal spine. The pathology of the two species was also found to differ: S. mansoni remained in the liver and laid its eggs there, whereas S. haematobium early in its development left the liver for the veins surrounding the bladder. Thus, 65 years after the discovery of the adult worm by Bilharz, the life cycle of snail fever was known. The discharged eggs, on reaching freshwater, release a swimming larva, the miracidum. Miracidia are short-lived, but if they encounter a suitable snail, they penetrate the soft tissues (usually the foot), migrate to the liver, and change in form (sporocyst); and for 6 to 7 weeks, by asexual reproduction, the numbers of parasites increase. During this time the snail sheds thousands of fork-tailed cercaria, which can swim and directly penetrate human skin, and in 5 to 8 weeks they develop into adult worms.

Snail fever, the disease

Schistosomes differ from other flukes (trematodes) in that the sexes are separate and they inhabit the blood vessels. The adult worms are ~10 mm in length, and the stouter males have a groove running lengthwise, called the gynecophoric canal, where the female normally resides (Fig. 3.2E). It is this groove in the male that is the basis for the worm’s generic name Schistosoma, meaning “split body.” Both males and females have two suckers at the head end of the worm, and the more anterior one surrounds the mouth. (Bilharz mistakenly took the two suckers for two mouths, and thus he called the worm Distomum, “two mouths.”) The schistosome adults, in sexual union, live in blood vessels (veins) close to the bladder and small intestine. Mating occurs in the gynecophoric canal, and then the paired worms move “upstream” into smaller veins, where the female worm deposits the fertilized eggs. The pathology of schistosomiasis is due not to the adult worms themselves but to the eggs. Each day hundreds of embryo-containing eggs move across the walls of the veins into the bladder or intestine, aided by the host’s inflammatory response, and in the process eggs become enclosed in a small tumor called a granuloma. It is the passage of eggs through the bladder wall that results in bleeding and gives the telltale sign of hematuria. Once in the bladder or intestine, the egg becomes freed of the granuloma and is eliminated from the body either with the urine or in the feces.

More than two-thirds of the eggs, however, fail to work their way out of the body and are washed back in the veins, and by means of the bloodstream they scatter throughout the body, where they accumulate in various organs. Accumulation is greatest in the liver and spleen. The piling-up of eggs blocks the normal blood flow, and this leads to tissue death. The egg also acts as an irritating foreign substance that the body attempts to wall off by surrounding it with a fibrous capsule. The egg-laden liver eventually becomes filled with scar tissue. In the bladder blood fluke, S. haematobium, the scarred areas block the migration of eggs through the lower bowel tissues, and more eggs are swept back into other sites. The earliest signs of infection, fever, chills, sweating, headache, and cough, occur within 1 or 2 months. Six months to a year later the accumulation of eggs produces organ enlargement, especially the liver and spleen; the enlarged and cirrhotic liver causes the abdomen to become bloated, appetite diminishes, blood loss leads to anemia, and there is dysentery (Fig. 3.3).

Figure 3.3 Two young boys infected with blood flukes

Schistosomiasis is an arithmetic disease: the severity of its symptoms and cumulative damage are directly related to the number of worms present, and the latter depends on the degree of exposure. In heavy cases there may be hundreds of worms, and the adults may live for 20 or 30 years. Clearly, with time and increased invasion by cercaria, a person becomes more and more debilitated. Yet over the centuries the adult inhabitants of areas where the disease is endemic, such as Africa, developed some measure of immunity largely as a result of continuous exposure; Europeans and Americans with no such immunity suffer more-severe symptoms as a result of higher burdens of worms.

Where snail fever is found

Wars and human migrations carried the blood flukes of the East African lakes to the Nile River, and from there it was distributed along the trade routes to most of the continents of the world. Although in 1902 Manson believed schistosomiasis to be a disease unique to Africa, he had to revise his thinking when he discovered an Englishman, who had resided in the West Indies but had never been to Africa, passing eggs with a lateral spine. In 1908, Piraja da Silva, living in Bahia, Brazil, wrote that the schistosome common in the Americas was probably introduced from Africa by West African slaves beginning as early as 1550. Indeed, Bahia was one of the ports of entry for the African slaves, and more recently it has been suggested that, under the Dutch (1630-1654), Recife may also have been an important slave entry point. Although snails native to the Caribbean and South America have been found to be effective vectors (and different from the snail species in Africa), snails introduced from Africa have also been important in transmission.

Schistosomiasis has not been eliminated. It is estimated that at present there are 240 million people infected with schistosomes and 700 million people at risk. Ninety percent of the cases are found in sub-Saharan Africa, resulting in >200,000 deaths annually. S. japonicum is found in Southeast Asia and the western Pacific, as well as China, the Philippines, and Indonesia. S. haematobium and S. mansoni are both found in 43 countries in Africa, but the latter species is also found in the Americas (Brazil, Suriname, Venezuela, and the Caribbean).

People who come to the freshwater pools to work, bathe, drink, wash clothes, and swim may also use the water for elimination of their body wastes. Individuals may be infected and reinfected almost daily as they paddle through the cercaria-infested waters that they have come to use as their outdoor toilets. Schistosomiasis remains one of Africa’s greatest tragedies. The highest incidence occurs in African children. In some instances, technology has expanded the numbers of cases. Indeed, every new irrigation scheme and each new dam may pose a new threat.

The Aswan High Dam of Egypt, begun in 1960 with Soviet financing and engineering and requiring 30,000 Egyptians toiling around the clock, was completed in 1971. The High Dam, by controlling the level of water in Lake Nasser, has brought electricity to many parts of Egypt as well as making four crops per year possible through year-round irrigation, but it has also created conditions favorable for the schistosome-carrying snails. Before High Dam construction there was already perennial irrigation in the Nile Delta and the prevalence of schistosomiasis was 60%, whereas in the 500 miles of river between Cairo and Aswan when there was annual flooding the prevalence was 5%. Some 4 years after the dam was completed, the average prevalence between Cairo and Aswan increased 7-fold (35%; range, 19 to 75%).

Schistosomiasis is generally a disease associated with agriculture, but it has also been a military problem ever since the days of Napoleon. During World War II, when U.S. troops stormed ashore on the Pacific island of Leyte in October 1944, they were unaware that in addition to being attacked by Japanese bullets they were also being invaded by the cercaria of S. japonicum. By January 1945 the first cases were diagnosed, and in the end 1,700 men were put out of action at a cost of 300,000 fighting man-days and $3 million. Five years later, 50,000 Chinese communist soldiers prepared for an invasion of Taiwan, but schistosomiasis became so widespread among the troops that the campaign was abandoned and the island was retained by Chiang Kai-Shek’s forces.

Where did schistosomiasis originate? It probably first occurred in animals living in the rain forests and lakes of East Africa and then spread together with its vector snails along the Nile and out into the Middle East and Asia via the trade routes. (Blood flukes occur in birds and mammals other than humans. Indeed, “swimmer’s itch,” or cercarial dermatitis, is found in lakes and along the seashore in Michigan, Minnesota, Wisconsin, New Jersey, and New England, as well as in other parts of the world, and is caused by cercaria [Fig. 3.2G] that normally infect aquatic birds and mammals. The skin rash and pustules are the result of their failure to continue their migration past human skin.)

Snail fever today

Diagnosis of schistosomiasis is made by the examination of stools and urine under the light microscope and the finding of eggs. Sometimes this visual test is supplemented by biopsy and immunologic methods. Preventive measures include education of the population regarding the means for preventing transmission, the treatment of infected persons, and the control of the snail vector using molluscicides. In some cases (e.g., growing rice), avoidance of contact may be impossible. Human exposure can be reduced, however, by the provision of a safe water supply for bathing and washing as well as by the sanitary disposal of human wastes. Other measures may be lining of irrigation channels with cement to discourage snails; intermittent irrigation of rice paddies to disrupt the life cycle; or storage of water away from snails for 2 or 3 days, a time that exceeds the survival time of the miracidia.

The earliest treatment for the disease, developed in 1918, required the intravenous administration of an antimony compound (tartar emetic). In 1929 intramuscular injections of another antimony compound, stibophen, were used, but the cure rates were not as good as with tartar emetic, and both drugs showed severe toxic reactions and sometimes resulted in death. Later, an oral drug, niridazole, was introduced (1964), but it wasn’t until the 1970s that a truly effective drug with low toxicity was developed: praziquantel (trade name: Biltricide). There is no preventative vaccine or drug.

The development of new drugs for the treatment of schistosomiasis can be a long and expensive undertaking. Further, determination of drug efficacy and safety may require extensive animal and human testing. One such heroic effort is worthy of mention. Claude Barlow, an American physician, volunteered for a chemotherapy trial and exposed his abdomen to 224 cercaria, and when cercarial dermatitis developed, he knew he had been infected. He came down with severe schistosomiasis, which required many intravenous injections of tartar emetic for cure. In his old age Barlow wrote: “even today I shudder every time I see a hypodermic needle.”

Today, with hindsight, it is easy to understand why those living in ancient Egypt were unable to control schistosomiasis, but why, 2,000 years later, are we still failing? There are certainly economic constraints such as the cost of pesticides to kill the snails and the cost of drugs, as well as the necessary infrastructure for providing clean water and sanitary disposal of wastes, but in the final analysis it is the habits of the human population that are of critical importance to the elimination of this disease. Since there is no animal reservoir, humans are required for the perpetuation of the disease. As long as infected individuals continue to urinate and defecate in the same waters where the vector snail lives, and to expose their bare skin, there will be blood fluke disease.