Читать книгу Forgotten People, Forgotten Diseases - Peter J. Hotez - Страница 18

Welcome the sunrise, come under the stars, work from dusk to daybreak

Our strength is boundless, our enthusiasm is redder than fire . . .

Be the river like a sea, drained clean it shall be . . .

Empty the rivers to wipe out the snails, resolutely to fight the big-belly disease.

WEI WEN-PO,1958

Schistosomiasis is a waterborne parasitic worm infection affecting up to 400 to 600 million people in developing countries.1 More than 90% of the cases occur in Africa, and today schistosomiasis is one of the most common parasitic infections in Africa. An additional 1 to 2 million cases each also occur in the Americas (primarily in Brazil) as well as in the Middle East (primarily in Yemen), and there are approximately 1 million cases of Asian schistosomiasis in China, the Philippines, and Southeast Asia (Fig. 3.1).1 Unlike the soil-transmitted helminths, which are nematodes, the schistosomes are a type of flatworm, also known as a trematode or fluke. As adult worms, schistosomes live in the bloodstream (and are known also as blood flukes), where they release eggs armed with a spine that produce serious disease either in the urinary tract or in the intestine and liver, depending on the particular species of parasite. Humans acquire schistosomiasis by direct contact with the larval stages (known as cercariae) that swim in freshwater. Prior to becoming cercariae, the immature developing and reproducing forms of these parasites spend a part of their life history living in various species of aquatic snails.

Few other infectious diseases have influenced history more than schistosomiasis has. Joshua’s curse and the abandonment of Jericho have been attributed to the disease.2 Schistosomiasis was well known to the ancient Egyptians, and it was a major scourge of Napoleon’s army during its disastrous military campaign in Egypt between 1798 and 1801.2 However, some of the most dramatic examples of the schistosome’s historical impact draw from postrevolutionary China during the second half of the 20th century. Shortly after the Chinese revolution in 1949, Mao Zedong (Mao Tse-tung) began planning a massive amphibious assault to bring Taiwan (then known as Formosa) under Communist control. While undergoing rigorous water training around the eastern tributaries of the Yangtze River, tens of thousands of People’s Liberation Army (PLA) troops were exposed to the infectious cercariae of Schistosoma japonicum, the parasitic larvae that live in the water and are shed by snails living in the wet mud along the riverbanks. Within weeks, tens of thousands of soldiers experienced the early acute phase of schistosomiasis, a condition known as Katayama syndrome, which can last for weeks and is characterized by fever, extreme fatigue, muscle pains, and coughing.3 As a result, the launch of the amphibious attack was delayed just long enough for the U.S. Seventh Fleet to enter the Strait of Formosa and abort a Communist takeover. These events are described in a 1959 Harper’s Magazine article titled “The Blood Fluke That Saved Formosa.”4

Figure 3.1 Distribution of schistosomiasis, worldwide, 2009. (See http://gamapserver.who.int/mapLibrary/Files/Maps/Global_schistosomiasis_2009.png [© 2010 WHO].)

Undoubtedly, the derailment of the PLA by a blood fluke transmitted by a snail made a deep impression on the Chinese Communist Party leadership. Beginning in 1955 on the order of Chairman Mao, a special nine-man committee on schistosomiasis was established and a seven-year plan for the eradication of the disease was launched.5 In 1958, beginning with the Great Leap Forward, millions of peasants were mobilized to the Yangtze River valley, where they drained the marshes and buried the “devil snails” under dirt or, in some cases, removed the snails individually with sticks.6 The quotation in the opening of this chapter is from a 1958 paper written by Wei Wen-po (the second-in-command of the nine-man committee) that appeared in the Chinese Medical Journal under the title “The People’s Boundless Energy during the Current Leap Forward.”7 Later, chemical agents to kill the snails were applied. Such low-technology interventions directed at snail control had an important impact and helped to reduce the overall prevalence of schistosomiasis from 12 million or more cases before the revolution to approximately 1.6 million cases by the mid-1980s.6 Mao himself wrote a poem about these successes entitled “Farewell to the God of Plague.” Today, there is a new concern that the completion of the Three Gorges Dam across the Yangtze River might help to establish new ecological niches for snails to thrive and reproduce, thereby causing a rebound in the number of cases of schistosomiasis, just as other dam projects on the Nile at Aswan and the Senegal and Volta rivers in sub-Saharan Africa have caused massive increases in snail populations and reemergence of the disease.8

In Egypt and elsewhere in East Africa, schistosomiasis has had an equally important historical impact. Schistosome eggs have even been recovered from Egyptian mummies dating from the 20th dynasty, around 1000 BCE.2 During the first half of the 20th century, more than half of the populations in some rural villages of the Nile Delta were infected with either Schistosoma haematobium or Schistosoma mansoni. Both forms of schistosomiasis were considered the scourge of the fellaheen, Egypt’s peasant agricultural laborers.9 It was said that hematuria, the bloody urine that results from S. haematobium infection, was so common among Egyptian children and adolescent boys that it was considered a form of male menstruation.9 The initial efforts to control schistosomiasis in Egypt and in neighboring Sudan (where the Gezira Scheme, one of the world’s largest irrigation projects, is located near the confluence of the Blue Nile and White Nile) were organized by the British, initially through multiple injections of toxic antimony compounds to cure the disease in humans and subsequently through widespread use of molluscicides, snail-destroying chemical agents distributed in the environment.10 During the 1960s, Bayluscide (known generically as niclosamide), a molluscicide developed by Bayer, was widely used but later largely abandoned because of price increases combined with a realization that it caused significant damage to fish and other wildlife. Subsequently, during the 1970s, newly discovered drugs, such as ambilhar and hycanthone, were used in large-scale treatment of schistosomiasis, but they too fell into disuse because of their toxicity and some unexplained deaths.10 Complicating Egypt’s schistosomiasis problem was the fact that many schistosome-infected individuals also contracted hepatitis C when contaminated needles and equipment were used to administer tartar emetic, an older and injectable antiparasitic drug that is now seldom used.10 Patients with schistosome and hepatitis C coinfections often suffered from a severe, progressive form of fibrotic liver disease.10 Finally, during the 1990s, widespread use of the anthelmintic drug praziquantel in a 14-year-long mass drug administration campaign, supported in part by the World Bank and the U.S. Agency for International Development (USAID), reduced the overall prevalence of schistosomiasis in Egypt to less than 10% of the population.10 In China, a 10-year World Bank initiative also supporting mass drug administration of praziquantel has resulted in similar dramatic reductions of schistosomiasis in the Yangtze River valley.10

Table 3.1 The major human schistosomes

Despite the successes in China and Egypt, today schistosomiasis still rivals hookworm infection as the most important helminth infection of humans. Urogenital schistosomiasis caused by S. haematobium is responsible for approximately 63% of the cases worldwide, while an intestinal and hepatic form caused by S. mansoni accounts for another 35% (Table 3.1).11 Less than 1% of the global burden of schistosomiasis results from the Cold War warrior S. japonicum.1 Several other minor species make up the remaining 1% of the cases. Almost all of the people infected with schistosomiasis live in Africa, with 29 African nations each harboring 1 million or more cases (Fig. 3.1).1 Outside Africa, only the nations of Brazil and Yemen have 1 million or more cases of schistosomiasis.1 In Brazil and elsewhere in the Americas, S. mansoni infection was likely introduced by a flourishing slave trade with sub-Saharan Africa that began in the 1600s.12

Humans contract schistosomiasis through freshwater contact with free-swimming cercariae (Fig. 3.2). Therefore, poor rural populations whose everyday activities involve fishing, bathing, or swimming in schistosome-contaminated waters or working in agricultural areas irrigated by contaminated waters are at the highest risk of infection.10,13 Almost 800 million people in developing countries live in proximity to either irrigated agricultural fields or dam reservoirs, where the risk of acquiring schistosomiasis is the highest.1

Schistosome cercariae have a forked tail that allows them to swim and ultimately to directly penetrate human skin. Following skin penetration, the cercariae lose their tail and undergo a number of biochemical changes that allow them to resist attack by the human immune system. The larval schistosomes (also known as schistosomulae) migrate through the lungs and over a period of approximately 1 to 2 months make their way to the portal vein of the liver, where they mature into adult male and female schistosomes.13 The paired worms ultimately migrate to their final destination, which for S. haematobium, the cause of urogenital schistosomiasis, is the small veins that drain the bladder and other pelvic organs, while S. mansoni and S. japonicum live in the mesenteric veins that drain the intestine.13 While living in the blood vessels, the adult schistosomes feed on blood, breaking down the hemoglobin components by using enzymes similar to those found in hookworms. Through evolution, the adult male and female schistosomes living in the bloodstream have developed remarkable mechanisms for masking their identity, including the accretion of host molecules on their surface. In this way, the schistosomes avoid attack by antibodies and cells of the human immune system.

Figure 3.2 Life cycle of human schistosomes. (From Public Health Image Library, CDC [http://phil.cdc.gov].)

The female worms subsequently produce hundreds of eggs daily.13 In order to continue the schistosome life cycle, the eggs ultimately require a mechanism to exit from the body. In the case of hookworm infection and other soil-transmitted helminth infections in which the parasites live in the gastrointestinal tract, the feces provide a straightforward path for the eggs to escape into the environment. In contrast, schistosome eggs have a more formidable challenge because they are present in the human blood vessels. As shown in Fig. 3.3, schistosome eggs are equipped with an ominous-looking spine that permits them to bore their way through the blood vessels and then into either the bladder or intestine from the outside. Through a combination of mechanical boring and the release of tissue-dissolving enzymes, the eggs gain access to either the lumen of the bladder or the intestine; they exit the body in urine or feces, respectively. When deposited in freshwater, the eggs live for about a week. They hatch and give rise to free-swimming ciliated forms known as miracidia, which seek out a suitable snail species. Upon entry into the appropriate snail, each miracidium can give rise to multiple progeny through asexual reproduction. Eventually, these progeny develop into cercariae that exit the snail.13

Figure 3.3 Spined eggs of S. haematobium (top) and S. mansoni (bottom). (Images from Public Health Image Library, CDC [http://phil.cdc.gov].)

Unfortunately, egg migration through human body tissues is not an efficient process, so many eggs become trapped in either the bladder and reproductive organs (S. haematobium) or intestine and liver (S. mansoni and S. japonicum). The trapped eggs cause mechanical damage and the rupture of small blood vessels, which lead to bleeding and the appearance of blood in either urine or feces. The eggs also trigger an inflammatory response composed of masses of human white cells and other host-derived components (known as granulomas), which can obstruct urine or blood flow. Because schistosomes can live for years in the small veins of the bladder and intestine, their constant release of eggs is associated with chronic blood loss leading to anemia, as well as damage to the bladder, kidneys, and reproductive organs (S. haematobium) or to the intestine and liver (S. mansoni). The combination of long-standing anemia, inflammation, and target organ damage causes growth retardation, undernutrition, and cognitive delays in children, as well as chronic abdominal pain, exercise intolerance, poor school performance, and reduced work capacity.13,14 Anemia and chronic inflammation also partially account for the developmental delays occurring in chronic pediatric soil-transmitted helminth infections.

Sub-Saharan Africa bears the greatest burden of disease caused by the schistosomes and almost all of the cases of S. haematobium infection. Figure 3.4 shows several children, each holding a cup of his or her reddened urine (schistosomiasis is sometimes known locally as “red-water fever,” as well as “snail fever”). Endemic hematuria from schistosomiasis was first recorded by a Western physician in 1798, by J. Renoult, a French army surgeon who accompanied Napoleon on his invasion of Egypt.2 Just as hookworm causes chronic blood loss in the intestine, leading to anemia, the chronic blood loss resulting from S. haematobium egg deposition in the bladder is a significant cause of anemia in Africa, particularly among adolescent children, who on average harbor larger numbers of schistosomes than do any other age group.13,14 We saw previously how chronic intestinal blood loss and anemia resulting from hookworm were associated with physical and mental delays in children. For urogenital schistosomiasis, the anemia results not only from urinary blood loss but also from other factors, including chronic inflammation. These processes also contribute to inhibition of physical and mental growth for the child. Other important contributors to the morbidity of urogenital schistosomiasis are the inflammatory granulomas that develop in the bladder. Severe bladder wall pathology occurs in an estimated 18 million people in Africa.11 When the bladder granulomas coalesce, they can obstruct urine flow and cause distension of the ureter and kidneys. This condition is known as hydronephrosis and occurs in approximately 20 million people in Africa as a result of S. haematobium infection.11 Long-standing hydronephrosis can lead to renal failure; this progression probably accounts for a significant number of the estimated 280,000 annual deaths from schistosomiasis.11 Another major consequence of chronic S. haematobium infection is its ability to predispose people to acquiring an unusual form of bladder cancer. Whereas most bladder carcinomas in the industrialized world are adenocarcinomas, S. haematobium infection is associated with a unique squamous cell carcinoma of the bladder. It is conjectured that the schistosome granulomas in the bladder may increase the exposure of the bladder epithelium to environmental carcinogens.13 Alternatively, the recent sequencing of the S. haematobium genome has also allowed scientists to search for carcinogenic molecules released by schistosome eggs.15 Still another important component of the morbidity of S. haematobium infection is involvement of the female reproductive tract. Up to 75% of women with this form of schistosomiasis develop fibrotic lesions known as “sandy patches” in the vulva, vagina, cervix, and uterus.16 Such lesions and sandy patches are associated with genital bleeding, pain on intercourse, infertility, and even clinical depression.16 Given that S. haematobium infection potentially affects hundreds of millions of people in sub-Saharan Africa, female urogenital schistosomiasis may actually be one of the most common gynecologic conditions on the African continent! This is but one way that schistosomiasis, like many neglected tropical diseases, disproportionately affects girls and women. Moreover, genital schistosomiasis lesions have recently been linked to a three-and fourfold increase in the transmission of HIV/AIDS in Zimbabwe and Tanzania, respectively, and presumably elsewhere in sub-Saharan Africa.16 From these and similar studies, there is considerable interest in looking at schistosomiasis control and prevention efforts in terms of their impact on HIV transmission in rural areas of Africa.16 The opportunity of exploring schistosomiasis elimination efforts as a back-door strategy for HIV/AIDS control is examined further in chapter 10.

Figure 3.4 Children in Niger with hematuria. (Photo courtesy of Juerg Utzinger, Swiss Tropical Institute.)

S. mansoni is also a significant cause of intestinal and liver pathology in sub-Saharan Africa and Brazil. The presence of eggs and granulomas in the intestinal wall, usually of the large intestine and rectum, is associated with bleeding and diarrhea, as well as with loss of appetite, while liver granulomas can cause inflammation and liver enlargement (hence the term “big-belly disease”).13 Chronic schistosomiasis of the liver can progress to fibrosis, splenic enlargement, and bleeding from the esophagus. Occasionally, severe bleeding can result in death. An estimated 8.5 million cases of liver disease result from S. mansoni infection in sub-Saharan Africa.11

Although snail control was the major tool used to effect an almost 10-fold reduction in the prevalence of S. japonicum infection in China, this approach has not been an efficient or very effective means for controlling either S. haematobium or S. mansoni in Africa and elsewhere. Failed efforts to control snails environmentally reflect the unique biology of the snail intermediate hosts of S. haematobium and S. mansoni as well as the epidemiology of these forms of schistosomiasis. In addition, the environmental toxicities of molluscicides preclude their constant and widespread use. Even in China, snail control has not been successful in eliminating the last remaining 840,000 cases in the Yangtze River valley.6

We saw previously (in chapter 2) how mass drug administration of benzimidazole anthelmintics is beginning to have an impact on the global burden of disease caused by soil-transmitted helminth infections. Today, the most effective means of controlling schistosome infections is mass drug administration of praziquantel to affected and at-risk human populations. Developed at Bayer, praziquantel was shown to be effective against all forms of schistosomiasis in multicenter trials, as evidenced by schistosome egg reductions or outright cures.10 Treatment of schistosome-infected children with praziquantel results in a number of health benefits similar to those experienced by children with soil-transmitted helminth infections who are treated with either albendazole or mebendazole, including improvements in growth and physical fitness, as well as reductions of anemia. In addition, multiple treatments with praziquantel can sometimes reverse both urinary tract and liver pathology, particularly if children receive these treatments early in their lives. Building on these breakthrough medical observations were the low-cost synthesis and production methods for manufacturing generic praziquantel by the Korean pharmaceutical company Shin Poong. These manufacturing improvements have dramatically reduced the price of the drug, possibly by as much as 90%.10 As a result, by the 1990s, it became possible to launch praziquantel mass treatment programs for schistosomiasis in several middle-income countries, including Brazil, China, Egypt, Morocco, the Philippines, Saudi Arabia, and Tunisia, as well as Puerto Rico.10,13,17 Several of these initiatives were funded by the World Bank. Praziquantel mass drug administration in these countries has been largely successful, particularly in Morocco and Puerto Rico, where the disease is close to being eliminated (zero transmission) partly because of parallel poverty reduction measures that were enacted.10

Despite the promise that praziquantel offers for controlling human schistosomiasis, up until recently it has not been made widely available.17 Previously (in chapter 2), we learned how in 2001, the 54th World Health Assembly adopted a resolution calling for treatment with a benzimidazole anthelmintic drug of at least 75% of school-age children at risk of acquiring schistosomiasis and soil-transmitted helminth infections by 2010. Based on the experiences and successes of mass drug administration of praziquantel, the resolution was written to include this drug along with either albendazole or mebendazole for the treatment of school-age children. In many regions of the developing world, especially in sub-Saharan Africa and Brazil, it is common for children to be polyparasitized with both soil-transmitted helminths (especially hookworm) and schistosomes,18 so that they could benefit from combination therapy with a benzimidazole anthelmintic and praziquantel. Unfortunately, the World Health Organization (WHO) estimates that in 2010 only about 33 million of the 236 million children at risk for schistosomiasis actually received praziquantel, just a little over 10%.19 The low drug coverage results from the absence of political will in expanding mass drug administration, together with limited availability of praziquantel. In response, in January 2012, the Bill & Melinda Gates Foundation partnered with the major pharmaceutical companies, the World Bank, WHO and other international agencies, and key nongovernmental organizations in a London Declaration to reaffirm support for control of neglected tropical drugs through mass drug administration.20 The announcement coincided with a commitment by a German company, Merck KGaA, to dramatically ramp up praziquantel donations.

A key implementing partner that provides technical assistance to the African health ministries in order to facilitate praziquantel administration (usually together with albendazole for soil-transmitted helminth coinfections) through mass drug administration is the Schistosomiasis Control Initiative (SCI), a public-private partnership established by Alan Fenwick at Imperial College London (www3.imperial.ac.uk/schisto). Previously, Fenwick had acquired a wide-ranging experience in large-scale control of schistosomiasis through his leadership in World Bank-and USAID-funded projects in Egypt and Sudan. Working in collaboration with ministries of health in almost a dozen sub-Saharan African countries as well as Yemen, together with WHO, the SCI facilitates once-yearly praziquantel treatments using donated praziquantel from Merck KGaA, as well as generic praziquantel from MedPharm and other sources. SCI operates through algorithms based on the schistosomiasis prevalence determined in local school surveys. The number of praziquantel tablets administered to each individual is based on an easy-to-use height pole that approximates a dose of 40 mg of drug per kg of body weight, and the delivery and distribution of praziquantel are carried out in health centers, in schools, or through community-based drug distributors.10

To date, SCI and its partners have made some impressive public health gains, scoring significant and dramatic reductions in either the prevalence or intensity of schistosomiasis in several African nations.21 Such successes and the prospects of expanded mass drug administration campaigns and ongoing donations of praziquantel have led some investigators to suggest that global schistosomiasis elimination is a potentially attainable goal.22 Indeed, in 2012 the World Health Assembly adopted a resolution that affirmed the feasibility of elimination.22 Here the term “elimination” refers to reduction in the prevalence of human schistosomiasis to the point where transmission has been interrupted, but unlike eradication, elimination may require ongoing implementation of public health control measures.

There are a number of important but still unanswered questions about the impact of praziquantel mass drug administration on sustainable poverty reduction in developing countries. Current population-based approaches with praziquantel are focused on reducing the morbidity of this condition in areas where high-intensity infections and serious urogenital, intestinal, and liver morbidities are present. However, it is unclear whether mass treatment will also reduce transmission and prevent reinfection in the community.23 This uncertainty is a serious concern, since ongoing low levels of schistosomiasis reinfection could lead to subtle but persistent clinical problems, including anemia, growth stunting, and diminished productive capacities.23 In addition, there are potential worries that frequent and periodic use of praziquantel could lead to anthelmintic drug resistance. These issues have prompted some nascent efforts to develop alternative or complementary control tools for schistosomiasis, just as they have for human hookworm infection. These activities include exploration of new drug development, including the antimalarial artemisinin, artemether, which also exhibits antischistosomal properties.24 Still another approach has been efforts to develop a recombinant vaccine for schistosomiasis, and several candidate vaccines have entered into early clinical trials (discussed in chapter 11).25 However, our major approach to schistosomiasis control still relies on mass drug administration of praziquantel or of praziquantel and albendazole or mebendazole in areas of schistosomiasis and soil-transmitted helminth coinfection. We will further explore (in chapter 10) how these treatments might link with mass drug administration for other neglected tropical diseases, including lymphatic filariasis, onchocerciasis, and trachoma.

Summary Points: Schistosomiasis

 Significant impact on the modern history of China and Egypt

 One of the most common and clinically important human helminth infections

 Schistosomiasis is a waterborne infectious disease transmitted by a snail intermediate host.

 Approximately 400 to 600 million cases worldwide, with more than 90% of the infections in Africa

 Children and adolescents are at highest risk. All forms of chronic schistosomiasis are associated with anemia, undernutrition and growth impairments, poor school performance, and reduced productive capacity.

 Urogenital schistosomiasis caused by S. haematobium accounts for approximately two-thirds of the schistosome infections in Africa. This form is responsible for hematuria, female genital schistosomiasis, and squamous cell carcinoma of the bladder. Genital lesions increase the risk of HIV/AIDS transmission.

 Intestinal and liver schistosomiasis caused by S. mansoni accounts for approximately one-third of the cases in Africa and 1 million cases of schistosomiasis in Brazil. This form is responsible for bloody diarrhea, abdominal pain, and liver involvement (hepatomegaly and fibrosis).

 The major approach to control of schistosomiasis today is mass drug administration of praziquantel. It has led to the near elimination of schistosomiasis in some middle-income countries and to significant morbidity reductions in some sub-Saharan African countries.