Читать книгу Forgotten People, Forgotten Diseases - Peter J. Hotez - Страница 14

As it was when I first saw it, so it is now, one of the most evil of infections. Not with dramatic pathology as are filariasis, or schistosomiasis, but with damage silent and insidious. Now that malaria is being pushed back, hookworm remains the great infection of mankind. In my view it outranks all other worm infections of man combined . . . in its production, frequently unrealized, of human misery, debility, and inefficiency in the tropics.

NORMAN STOLL, 1962

The neglected tropical diseases (NTDs) are the most common infections of the world’s poorest people, and the soil-transmitted helminth (STH) infections are the most common NTDs. The word helminth comes from the Greek έλμίνς, meaning “worm,”1 and the phrase soil-transmitted refers to the human acquisition of these worms through contact with soil contaminated with either parasite eggs or immature larval stages. STHs are also sometimes called intestinal helminths or intestinal worms because the adult stages of the parasite live in the human gastrointestinal tract. The STHs are also nematodes, a type of parasitic worm distinguished by their elongate and cylindroidal shape.

The three most important STH infections of humans, based on their prevalence and global disease burden, are:

 Ascaris infection (also known as roundworm infection or ascariasis)

 Hookworm infection (hookworm)

 Trichuris infection (whipworm infection or trichuriasis)

Together, these helminth infections afflict more than 1 billion people in developing countries.

Humans have been infected with STHs since ancient times. We know this from accurate descriptions found in Egyptian medical papyri and the writings of Hippocrates in the 5th century BCE, including reports of large Ascaris roundworms being expelled from infected people and of the characteristic pallor and sallow complexion of people with hookworm.1 In addition, STH eggs have been recovered from coprolites, mummified feces thousands of years old, found in both the Old World and New World.1 Today, an estimated 800 to 900 million, 600 to 700 million, and 500 to 600 million people are infected with ascariasis, hookworm, and trichuriasis, respectively (Table 2.1).2 More often than not, a single individual living in a developing country, especially a school-age child, is infected with two and sometimes all three types of STH parasites simultaneously. Practically speaking, this observation means that the intestines of hundreds of millions of children living in Africa, Asia, and the Americas harbor a menagerie of worms. Harold Brown, the late former parasitology professor at Columbia University College of Physicians and Surgeons, frequently referred to Ascaris, Trichuris, and hookworms as “the unholy trinity” to indicate that it was extremely common for a child to be infected with all three parasites simultaneously. Typically, Ascaris roundworms and hookworms inhabit the small intestine, while Trichuris whipworms inhabit the large intestine.

How can we fathom the notion of approximately 1 billion people infected with STHs? To understand this concept better, we need to travel to a developing country where STH infections are endemic, meaning that the infections are constantly present in a particular region. Figure 2.1 shows children living in a rural village in Minas Gerais State, Brazil. The families of these children are mostly subsistence farmers involved with cultivation of manioc and beans. Looking at these children, one might not think that they appear terribly ill, unless one examines them more closely. The STH-infected children living in this Brazilian village are stunted in both weight and height because they are not growing normally. Moreover, they also do poorly on tests of cognition, memory, and intelligence. There is now strong evidence that such physical and mental disabilities result from the presence of intestinal worms.3

Table 2.1 The “unholy trinity”

Figure 2.1 Children (left) living outside the Brazilian village of Americaninhas, Minas Gerais State (right). About 75% of people living in the area are infected with hookworm. The effects of the disease—malnutrition and anemia—are worse in children. (Photos of the children courtesy of Brigid McCarthy of National Public Radio [© 2005 NPR].)

The reason we know that most of the children of Americaninhas, Minas Gerais State, Brazil, harbor intestinal worms is that we can diagnose their STH infections by examining their feces under a microscope. The adult male and female roundworms, whipworms, and hookworms mate in the intestines and produce eggs that exit the body in feces. Each type of STH produces characteristically shaped eggs that are easy to identify through microscopy. If we now do this test for all children in this particular rural Brazilian village, we get a result that is shown in Fig. 2.2, in which more than 70% of the children between the ages of 5 and 11 are infected with Ascaris worms and hookworms. It turns out that we can repeat this study in almost any rural Brazilian village or indeed almost any rural village in the tropical regions of the Americas, including Central America, and probably obtain a similar result or find that just as many children are also infected with Trichuris whipworms. Indeed, if we were to conduct fecal examinations on most of the rural villages in sub-Saharan Africa, on the Indian subcontinent, or in Southeast Asia, really wherever people live in poverty and depend on subsistence agriculture and where the soil and climate are suitable for survival of the parasite eggs and immature larval stages (typically the warm and moist soil of the tropics), we would find a similar paradigm of extraordinarily high rates of STH infections. Such observations suggest how it can be that hundreds of millions of people harbor the unholy trinity in their bellies.

Figure 2.2 Prevalence of STH infections among school-age children in Americaninhas, Brazil. (Data courtesy of Jeff Bethony and David Diemert, Human Hookworm Vaccine Initiative; modified from graph prepared by Sophia Raff.)

Beginning in the late 1980s, parasitologists of the Chinese Academy of Preventive Medicine, now known as the Chinese Center for Disease Control and Prevention, conducted a 4-year study of intestinal parasites on an almost unimaginable scale by performing fecal examinations on 1,477,742 individuals in every province of China. The results were impressive and demonstrated that approximately 531 million cases of ascariasis, 212 million cases of trichuriasis, and 194 million cases of hookworm infection had occurred in that country.4 In collaboration with the Institute of Parasitic Diseases in Shanghai, I began working in China shortly after the completion of this nationwide survey of parasites. What particularly impressed me was the very tight link between high endemicity of STH infections in rural China and the level of economic underdevelopment.5 Wherever rural poverty was extreme and the villagers were engaged in subsistence agriculture, and provided there were suitable moisture and warmth, it was almost guaranteed that high levels of hookworm and other STH infections were present. Conversely, in areas of rapid economic gains, the STH infections disappeared. For instance, during the late 1990s when I visited a village in Jiangsu Province, not too far from Shanghai, there had been a steep decline in the prevalence of hookworm from just a decade previously.6 The decline coincided with the building of new factories such that fewer villagers were engaged in agricultural activities. Moreover, there was even a new Kentucky Fried Chicken franchise, as well as a pirated version with the same red-and-white logos—called KCF instead of KFC! Hookworm occurs only in the setting of poverty, and in a sense, the factory, KFC, and KCF represent indicators of economic development.

As shown in Fig. 2.3, the relationship between STH prevalence and poverty is extremely tight,7 and I believe that it is feasible to develop a “worm index” of economic development as a poverty indicator. However, a clear understanding of the specific mechanisms underlying the link between a high prevalence of STH infections and poverty is still somewhat elusive. At least three possible factors linking poverty to STH infections have been identified so far, including (i) inadequate sanitation, because survival of the environmental stages of STH parasites depends on the deposition of human feces on soil; (ii) poor housing construction, because dirt floors allow propagation of STHs in households, whereas cement floors prevent parasite transmission; and (iii) inadequate access to essential medicines, because better-off families can afford deworming drugs.8 Urbanization is also a potent factor in reducing the prevalence of STH infections. In eastern China, for example, rapid economic growth has brought with it a significant decline in prevalence, whereas in the poor and largely rural southern and southwestern provinces of China, such as Hainan, Sichuan, Yunnan, Guizhou, and Guangxi, hookworm and other STH infections remain highly endemic.5,8

Figure 2.3 The relationship between prevalence of hookworm and poverty. The socioeconomic status of 94 countries was assessed according to a number of commonly used indicators, with poverty measures divided into quartiles including the poorest (first quartile), very poor (second quartile), poor (third quartile), and least poor (fourth quartile). (Original from de Silva et al., 2003; later modified for Hotez et al., 2005.)

In addition to their enormous global prevalence and their intimate link with rural poverty, another important feature of STH infections is their predilection for affecting children more than adults. For reasons that are not well understood, children between the ages of 4 and 15 on average harbor larger numbers of STHs than do any other group; i.e., children are wormier than adults. This propensity is particularly true for Ascaris roundworms and Trichuris whipworms, less so for hookworms. For example, shown in Fig. 2.4 is a little girl from Paraguay who simultaneously is emaciated and has a distended abdomen. It is sometimes possible to gently palpate the abdomens of children like her and feel the presence of worms in their intestines. Figure 2.4 also shows the Ascaris roundworms that she expelled after treatment with an anthelmintic drug (a process often referred to as deworming). It is easy to grasp how this girl could get into medical trouble if the roundworms were allowed to remain and obstruct the intestine or in some cases migrate from the intestine and into the liver or pancreas.

Figure 2.4 (Left) Little girl from Paraguay with severe Ascaris worm infection. (Right) Worms expelled after anthelmintic treatment. (Photos courtesy of Nora Labiano; reproduced from Despommier et al., 2006.)

Although such clinical pictures are dramatic, they actually represent only a small portion of the global pediatric pathology caused by STHs. Far more important is the observation that in hundreds of millions of children the STHs stunt physical growth, physical fitness, and development. These processes probably operate at least partly through parasite-induced malnutrition, as all three major STHs can live in the intestines of children for years, where they can rob children of essential nutrients. For example, Ascaris roundworm infections most likely retard growth by impairing the digestion of protein, causing the malabsorption of fat, lactose, and vitamin A, as well as reducing appetite; Trichuris whipworm infections also result in reduced appetite, as well as in protein losses; and hookworms impair growth by causing blood loss that leads to profound protein and iron losses and ultimately to anemia.9 Through these mechanisms, it is possible that STHs represent the world’s leading cause of growth retardation and stunting!

Moreover, the unholy trinity also adversely affects the neuropsychiatric activities of children, in turn damaging school performance and reducing school attendance.10,11 The mechanisms by which school performance is impaired are not well established, but a number of clinical studies have shown that STHs can adversely affect cognition and memory and in some cases possibly lower intelligence. 11 Therefore, chronic infections with STHs destroy the lives of children not by shortening their lives but instead by impairing their physical growth, mental development, and ability to learn in school. Each of the NTDs not only occurs in the setting of poverty but also promotes poverty. In the case of STH infections, roundworms, whipworms, and hookworms promote poverty primarily through their impact on overall child development. Presumably, these processes account for the observation that chronic infection with hookworm during childhood is associated with a 43% reduction in future wage-earning capacity (similar studies for ascariasis and trichuriasis are not yet available).12 Therefore, STH infections have a huge impact not only on health but also on education, and like other NTDs they are economic threats.

As suggested by the opening quotation from the late Norman Stoll, hookworm is probably the most significant STH. New Global Burden of Disease 2010 information (published at the end of 2012) confirms this observation, with preliminary indications that hookworm is responsible for almost two-thirds of the disability-adjusted life years (DALYs) lost from all of the STH infections.13 Hookworms are 1-cm-long parasites that live in the small intestine, where they suck blood from the small blood vessels lining the gut mucosa and submucosa. Approximately 700 million people, about one-half of the world’s poorest people, are infected with hookworm. The greatest concentration of cases occurs in rural areas of sub-Saharan Africa, East Asia and the Pacific region, the Indian subcontinent, and tropical regions of the Americas, especially Brazil and Central America (Fig. 2.5).2,14 Infection rates are often particularly high in coastal areas, an observation that most likely reflects the unique requirements of the soil-dwelling environmental stages of these parasites.

Figure 2.5 Global distribution of human hookworm infection. (From Hotez et al., 2005.)

Nearly as striking as the high prevalence of hookworm in developing countries is the almost complete absence of hookworm in highly developed countries, including the United States. However, up until the 1930s, hookworm infection (as well as many other NTDs, such as malaria and typhoid fever) was endemic in the southern United States.15 Shown in Fig. 2.6 is a map of the distribution of hookworm in the American South during the first decades of the 20th century, when high rates of hookworm infection occurred along the Gulf Coast and the Atlantic seaboard (the basis for the high rates of hookworm in coastal areas will become clearer when we discuss the hookworm life cycle). In some regions where more than 50% of the children were infected, it was shown that hookworm was a major reason why children were malnourished, why their growth was stunted, and why they did poorly in school and were prevented from reaching their full economic potential.12,15

After Charles Wardell Stiles and Bailey K. Ashford identified Necator americanus as the predominant hookworm in the United States, it became known as the “germ of laziness” or the “vampire of the South.”1,15 It is believed that hookworm was introduced into the United States when N. americanus was imported by infected slaves from sub-Saharan Africa during the 17th, 18th, and 19th centuries.1,15 Up until the 1950s, hookworm was also common in Japan and South Korea. In each of these now developed countries, reductions in the prevalence of tropical infections occurred primarily because of overall reductions in poverty and a shift to a more urbanized economy. In her book Malaria, Poverty, Race, and Public Health in the United States, the medical historian Margaret Humphreys argues that the Agricultural Adjustment Act and other New Deal legislation, which Congress passed in 1933, promoted rural depopulation by providing investment capital for the purchase of machinery, which took agricultural workers out of cotton and tobacco production.16 Such legislation caused landlords to tear down rural shacks and forced former dwellers to move either north or into southern cities.16 There is a common misconception that during the first 2 decades of the 20th century, the Rockefeller Foundation and its forerunner, the Rockefeller Sanitary Commission, eradicated hookworm in the American South and later in parts of Asia and South America through a combination of aggressive sanitation and the widespread distribution of shoes. For reasons that we will see below, it turns out that shoes are not an effective hookworm prevention measure, while sanitation in the absence of parallel economic development frequently has little impact on the transmission of STH infections.17 Instead, rural depopulation, urbanization, and economic development in the United States during the 1930s and in Japan and Korea in the years following World War II were probably the major elements leading to control of STH infections. In Asia, control was further hastened through widespread deworming by using first-generation anthelmintic drugs. Similar changes in human ecology probably account for the reductions observed in eastern China over the last 2 decades. Therefore, urbanization and economic development represent two of the most powerful forces responsible for the control of hookworm infection and other NTDs. Far more than the Sanitary Commission, the major health legacy of John Rockefeller was his foresight in establishing The Rockefeller University as a biomedical research powerhouse and in endowing the first generation of public health schools in the United States, beginning with the flagship school at Johns Hopkins University.

Figure 2.6 Distribution of human hookworm infection in the American South at the turn of the 20th century. The map displays the rates of hookworm infection among children by county groups. Red areas indicate the highest infection rates, followed by orange, yellow, and green. (Data from Bleakley, 2006.)

Humans become infected with hookworm through contact with infective larvae that live in the soil.18 The major cause of human hookworm infection is the nematode parasite N. americanus, although a second but less common species, Ancylostoma duodenale, also causes hookworm infection. The life cycle of N. americanus is shown in Fig. 2.7. Soil-dwelling infective hookworm larvae exhibit the ability to directly penetrate human skin. The larvae are less than 1 mm long (Fig. 2.8) and are therefore largely invisible to people working in the fields or children playing on the ground. Larvae enter through any exposed skin, including the hands, the arms, the buttocks, the legs, and yes, sometimes even the feet. The ability of N. americanus larvae to penetrate all aspects of the skin explains why shoes have minimal if any impact on reducing the hookworm prevalence in affected communities. The higher rates of hookworm infection in coastal areas reflect the sandy soils present in these regions. Hookworm larvae can migrate through sandy soils better than through soils with a high clay content.19

Figure 2.7 Life cycle of the hookworm N. americanus. (From Hotez et al., 2005.)

Figure 2.8 An adult hookworm. (Photo courtesy of David Sharf [http://www.electronmicro.com].)

It is common for people exposed repeatedly to hookworm larvae in the soil to acquire a pruritic (itchy) inflammatory condition of the skin known as ground itch or dew itch. The larvae then follow a 5- to 8-week migratory path through the body tissues, which includes an obligatory migration through the lungs that results in a cough (in contrast, when Ascaris larvae migrate through the lungs, they cause wheezing and other allergic symptoms that resemble asthma). Eventually, the infective hookworm larvae pass up the respiratory tree, crawl over the epiglottis, and are swallowed, before they enter the intestine and develop into adult hookworms. As the larvae develop into adult worms, they initially cause a painful eosinophilic enteritis syndrome. Subsequently, the pain subsides and mature parasites proceed to feed on blood. Each adult hookworm has the ability to fasten deeply to the inner lining of the intestine and extract blood. The parasite lyses red blood cells and digests the hemoglobin component.20 While feeding, the adult male and female hookworms mate and the female hookworm sheds thousands of eggs daily, which exit the body via the feces. In poor rural environments lacking adequate sanitation, either promiscuous defecation occurs or, in some societies, human feces are applied as fertilizer for crops (sometimes referred to as night soil). When feces are deposited on soil with adequate warmth and moisture, the eggs hatch and give rise to immature larvae that molt to become infective larvae.

People infected with hookworms become sick because of intestinal blood loss. The presence of as few as 25 N. americanus hookworms in the intestine is sufficient to cause about 1 ml of blood loss per day.21 This amount of blood contains approximately 0.5 mg of iron, representing roughly a typical child’s daily iron requirement. Therefore, hookworms essentially rob growing children of their daily iron and, as a result, cause iron deficiency anemia.21 Higher hookworm loads cause even more blood loss and more-profound anemia. Therefore, the disease resulting from chronic hookworm infection (sometimes referred to as hookworm disease) is long-standing iron deficiency anemia, which in children is responsible for growth retardation and intellectual and cognitive impairments. Because children tend to have low iron reserves from the outset, they are particularly vulnerable to hookworm-associated blood loss. Blood is also rich in protein, so that chronic blood loss can result in profound protein malnutrition, which is associated with edema of the face and limbs (Fig. 2.9). Many such children acquire a yellowish or sallow complexion; in several cultures, hookworm is known as the “yellow disease” or the “yellow puffy disease” (in Chinese, huang zhong bing, and in Brazilian Portuguese, amarelao). In antiquity, there are numerous references to the yellow disease, and there is an older term in the English medical literature, chlorosis, that refers to this condition.18 Another unusual feature of chronic hookworm infection is pica, an appetite for consuming clay and other bulky substances. Referring to hookworm, Hippocrates described a syndrome in which “the skin is yellow, the intestine disturbed, and the person has an appetite for eating clay,” and there are numerous references to clay eating in early Southern culture.1 It has been suggested that eating of clay represents an effort to replace iron stores because of its high iron content.1

Figure 2.9 Severe hookworm disease. The child is both pale and edematous, thus reflecting severe loss of both iron and protein. (Image from Public Health Image Library, CDC [http://phil.cdc.gov].)

Hookworm is also an important health threat during pregnancy, and an estimated 44 million pregnant women worldwide suffer from hookworm infection. Additional estimates indicate that almost 7 million pregnant women in sub-Saharan Africa (almost one-third of all pregnant women) are infected with hookworm.22 Pregnant women typically have low iron reserves and are often iron deficient to begin with because of the iron demands of a growing fetus. There is a strong link between the added iron losses and anemia that result from hookworm and adverse maternal-fetal outcomes such as neonatal prematurity, low birth weight, and increased maternal mortality.21,22 Among agricultural laborers, chronic hookworm iron deficiency results in impaired worker productivity and productive capacity. In the early part of the 20th century, the Brazilian writer Monteiro Lobato created the now famous character of Jeca Tatu, a laborer who is always lazy and lacking in energy until he is cured of his hookworm infection and then goes on to champion social causes (Fig. 2.10). The chronic disabilities associated with impaired child development, poor pregnancy outcome, and reduced worker productivity account for the observation that hookworm costs more healthy life years lost through disability annually than any other parasitic worm infection.23

Given that shoes do not protect against hookworm infection, what might be our options for controlling or preventing hookworm in developing countries? The sanitary disposal of human feces by increased use of latrines could under some circumstances dramatically reduce the prevalence of hookworm and other STH infections. However, the best evidence to date is that unless it is accompanied by substantial poverty reduction measures and urbanization, the isolated use of latrines has minimal impact on the transmission of hookworm or other STH infections.17 Currently, the most effective approach to the control of STH infections is through deworming of large populations through mass drug administration of a specific anthelmintic with the ability to expel all three major parasite species. This approach is the first example that we will describe in which mass drug administration (frequently abbreviated as MDA) is used for the large-scale control or elimination of an NTD.

Figure 2.10 (Left) A Brazilian worker with amarelao, chronic hookworm infection (from Klintowitz, 1989; TAM Airlines Magazine). (Right) Jeca Tatu.

For the STHs, anthelmintic drugs belonging to the benzimidazole class (sometimes referred to as benzimidazole anthelmintics or BZAs) are primarily used in a single dose for purposes of mass deworming. The two major available BZAs are albendazole and mebendazole. Both drugs are available as low-cost generic products, and in some cases BZA donations are being organized through two programs housed at the Task Force for Global Health in Atlanta, including a Johnson & Johnson program for mebendazole donations and a GlaxoSmithKline program for albendazole. Because school-age children are particularly at risk for heavy STH infections with large numbers of worms, this group is the major one targeted for global deworming efforts. Frequent and periodic deworming of school-age children with BZAs has been shown to result in a number of pediatric health and nutritional benefits, including improvements in appetite, physical fitness, and physical growth, as well as improved iron status and reductions in anemia.11,24 Deworming also produces neuropsychiatric progress, including positive intellectual and cognitive effects, such as improvements to short-term and long-term memory, problem solving, language, and cognition.11,24 Michael Kremer and Ted Miguel, economists at Harvard University and the University of California, Berkeley, respectively, have recently confirmed the benefits of deworming in promoting educational advancement, while additional economic analyses conducted by Kremer and Miguel together with Sarah Baird and Joan Hicks, as well as Hoyt Bleakley of University of Chicago, suggest that these effects may also translate into economic benefits for the community.10,11,24

Every May, the world’s ministers of health meet at the annual World Health Assembly, held at WHO headquarters in Geneva, Switzerland. At the 54th World Health Assembly in 2001, a resolution was adopted (Resolution 54.19) that urged member nations to attain a minimum target of regular deworming of at least 75% and up to 100% of all at-risk school-age children (www.who.int/wormcontrol). Since then, there has been heightened advocacy by the WHO and other international agencies for the administration of BZAs, typically a single dose of either albendazole or mebendazole, on a large scale. Increasingly, annual deworming is being practiced in schools because of the cost-effectiveness and efficiencies of having teachers rather than health care practitioners administer anthelmintic drugs.25 This approach includes using schoolteachers who are specially trained to deliver the deworming tablets alongside health education messaging.24 In many African and Asian countries, deworming is linked with school feeding programs sponsored by the World Food Programme (www.wfp.org) and through the FRESH Partnership (Focusing Resources on Effective School Health), an interagency initiative of the World Bank, UNICEF, UNESCO, and WHO (www.freshschools.org), as well as nongovernmental organizations such as the Partnership for Child Development (www.child-development.org) and Deworm the World (www.dewormtheworld.org).24 Such interventions can be achieved for extremely low costs. For example, in Ghana and Tanzania, hundreds of thousands of children have been treated for as little as US$0.03 and $0.04 per capita.24,25 In addition to the fact that the BZAs are often donated for free, another reason that the costs of school-based deworming are so low is that the excellent safety profile of a single dose of a BZA allows children to be treated regardless of whether they are infected with STHs. Instead, once it is established that the overall community prevalence of STH infections exceeds 50%, it no longer is necessary to conduct fecal examinations on each child. Authorities can then blanket the school with a single dose of either mebendazole or albendazole. This practice eliminates the high cost of bringing trained microscopists and laboratory equipment to the school. I believe that the advocacy efforts of two individuals, namely, Lorenzo Savioli at WHO and Don Bundy, now at the World Bank, were especially instrumental in promoting global deworming and advancing the agenda leading to Resolution 54.19.26

More than 300 million children in 77 countries received low-cost deworming in 2010.27 While this number is impressive, it is still far short of the almost 900 million children who would need to be treated annually in order to meet the targets specified by World Health Assembly Resolution 54.1927 (Fig. 2.11). Because many school-age children do not attend school in developing countries, as an alternative or complementary approach to school-based interventions, many children are being targeted worldwide through community-based interventions, such as child health days. In such programs, deworming is linked to vitamin A distribution as well as to some immunizations, such as measles vaccinations.24 Child health days and other community-based interventions are particularly suitable in regions of STH infection endemicity where preschool children, i.e., children under the age of five, also suffer from moderate and heavy infections. By some estimates, almost 200 million children have received vitamin A in more than 50 countries,24 so that this mechanism provides an added opportunity to scale up deworming. Also, as pointed out earlier, in some developing countries pregnant women are at high risk for hookworm infection, and the WHO and other international agencies have therefore expanded their recommended targets to include this group in areas of high transmission.

Although for most school-based and community-based interventions a single dose of either mebendazole or albendazole is provided on an annual basis, in areas of intense transmission deworming may need to be conducted more frequently. STH reinfection can occur over a period of just a few months, so that sometimes two or three dewormings must take place in a single year. Currently, the WHO recommends two or three deworming treatments annually in areas of high prevalence (typically greater than 70% prevalence) or high intensity (where more than 10% of the population have moderate or heavy infections).

Figure 2.11 Proportion of children (1 to 14 years of age) by country requiring preventive chemotherapy for soil-transmitted helminthiases, worldwide, 2010. (See http://gamapserver.who.int/mapLibrary/Files/Maps/Global_STH_2010.PNG [© 2011 WHO].)

When frequent and periodic dewormings are required in order to control STH infections for large populations, there are concerns that STH parasites, like any other infectious agent, could over time become resistant to either mebendazole or albendazole. Indeed, BZA resistance is now widespread among intestinal helminth parasites of sheep and cattle in Australia, New Zealand, South America, South Africa, and elsewhere in the Southern Hemisphere.28 The mechanisms by which BZA resistance occurs will be discussed later (in chapter 11). To date, there is no convincing evidence of the emergence of drug resistance to the BZAs used for human STH infections. However, a systematic review conducted by Jennifer Keiser and Juerg Utzinger from the Swiss Tropical and Public Health Institute revealed that single-dose mebendazole currently exhibits a cure rate for human hookworm infection of only 15%, with egg count reductions for N. americanus hookworm infections ranging from 0 to 68%.28 Thus, while albendazole is still generally effective for N. americanus hookworm infection, single-dose mebendazole can no longer be considered a standard treatment for hookworm infection. Today, the high rate of drug failures for single-dose mebendazole and high rates of STH infection in areas of high transmission, coupled with emerging evidence of BZA resistance in animal nematodes, have led to international calls for increased monitoring of the effectiveness of the BZAs and for the development of new-generation STH drugs.

Given the enormous health and educational benefits of deworming, I believe that we should try to do everything possible to scale up the use of BZAs in developing countries. We now have in hand some very promising geostatistical tools for increasing the efficiencies of deworming in resource-poor settings.29 At the same time, however, we must try to develop backup control tools. Unfortunately, the absence of a commercial market for such drugs has hampered a substantive research and development effort on this front. As an alternative or complementary approach to STH control, there has been a concerted effort to develop a recombinant anthelmintic vaccine, which would prevent reinfection following deworming.30 In chapter 11, I will discuss the efforts of our nonprofit product development partnership, known as the Human Hookworm Vaccine Initiative, to develop a new hookworm vaccine as an important antipoverty measure.

Summary Points: “The Unholy Trinity”

 STH infections are caused by intestinal worms, with Ascaris roundworms, Trichuris whipworms, and hookworms being the most common.

 Ascariasis, hookworm infection, and trichuriasis are the world’s most common NTDs.

 STH infections are highly prevalent in sub-Saharan Africa, Asia, and the Americas, especially in areas where rural poverty overlaps with tropical environments and adequate rainfall.

 Children typically exhibit heavier STH infections with higher worm burdens than do adults.

 The STHs live for years in the gastrointestinal tract.

 In children, chronic STH infections impair physical growth and development as well as cognition, memory, and school performance. Therefore, STHs produce educational deficits as well as ill health. These poverty-promoting features probably result from parasite-induced malnutrition.

 Hookworms cause malnutrition by producing intestinal blood loss, which leads to iron deficiency anemia, especially in children and pregnant women with low underlying iron reserves. The DALYs lost to hookworm infection rank the highest for any worm infection.

 Global control of STH infections currently focuses on morbidity reductions through frequent and periodic deworming with BZAs. School-based deworming is being frequently emphasized in order to target at-risk children.

 There are both theoretical and actual concerns about BZA drug resistance; a human hookworm vaccine is under development.