Forgotten People, Forgotten Diseases. Peter J. Hotez
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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,