Deworming the World

Abstract

Worms or helminths have historically infected more than half the world's population, but were largely neglected by medical science and public health interventions because they were considered non-fatal and of minimal clinical significance. During the 1980s, several oral drugs that were originally developed for veterinary use were discovered to cure, in a single dose, most human helminth infections. This allowed the first systematic population-based studies of the morbid sequelae of chronic worm infection and their potential reversibility after treatment. Based on these studies, we now know that almost all infected children and many adults, particularly pregnant and lactating women, suffer adverse effects from worms, including growth stunting, anemia, decreased cognitive development, and poor birth outcomes as well as poor school and work performance. Worm-infected people also respond less well to vaccinations and are more susceptible to several co-conditions such as HIV and cirrhosis. Based on these findings, several vertically organized national control programs were initiated in developing countries against schistosomiasis and the soil-transmitted helminths (hookworm, ascariasis, and whipworm). In 2005, the impact of helminth infections was redefined in terms of disability-adjusted life years (DALYs). All worm infections amenable to population-based mass chemotherapy are thought today to cause 30 million DALYs worldwide or very close to the worldwide impact of tuberculosis (TB) or malaria. In addition, almost all worm-induced DALYs are potentially reversible or preventable with periodic treatment. In 2001, the World Health Assembly advocated for mass deworming to reach 75% of the at-risk school-aged children of the world, but by 2011 only 13% had been reached. The recent large donations of anti-helminth drugs by major pharmaceutical companies linked to the inclusion of the “neglected tropical diseases” into current priorities for AIDS/TB and malaria now represent the best hope for closing this gap.

INTRODUCTION

Helminths (worms) are very common human pathogens with ascaris, hookworms, and trichuris (whipworm) infecting more than a billion individuals each worldwide (1). Because these infections are only rarely fatal, they have for many years been considered “less important” human pathogens. Worm-induced morbidity such as intestinal obstruction with ascariasis or rectal prolapse from whipworm were considered rare and rarely life threatening (2). Only hookworms were recognized early on as causing a significant amount of iron deficiency anemia in a high percentage of the infected population (3).

Schistosomiasis affects fewer individuals (200 &endash; 300 million worldwide), but because approximately 1% of the infected population dies each year from direct or indirect effects of this chronic worm infection, it has historically received more scientific and public health attention (4). But even with schistosomiasis, severe morbidity and mortality were considered rare events, found in only a small percentage of heavily infected individuals (5). As a result, when health priorities were recalibrated in the 1980s based on disability-adjusted life years (DALYs), schistosomiasis and many of the soil-transmitted helminths ended up appearing to have relatively little clinical significance worldwide (6).

WORMS AND SUBTLE MORBIDITY

Fortunately, in the 1980s, several oral drugs were developed and commonly used in veterinarian practices that were found to be highly effective against these human worm pathogens. These included praziquantel and albendazole (7). This development, for the first time, allowed the systematic examination of the impact of these parasitic infections on more subtle aspects of morbidity, such as childhood growth stunting (8–10), delayed intellectual development (11–12), cognitive impairment (13), decreased function work capacity (14), and anemia (15–16).

Through this research, it became clear that a significant amount of morbidity induced by worms was based on a complex interaction between the host and the specific parasite. In children, for example, the growth stunting effect of parasites was most marked in early childhood or during the adolescent growth spurt; and it depended (to a large extent) on the baseline nutritional status of the population, i.e., populations which already had moderate to severe malnutrition, suffering disproportionately from the same degree of parasitic infection (17). Fortunately, growth stunting could often be reversed with curative chemotherapy, but it was critical to keep the child free of rapid reinfection (17). Cognitive impairment from parasitic infections was also most pronounced in the youngest children and could often be reversed rapidly, following parasitological cure.

Anemia was perhaps the most complex of the worm-induced morbidities. As one might expect, the impact of worms on anemia was greatest in populations who were already iron deficient and among women and growing children of both sexes. With infections, such as hookworm, anemia was principally driven by blood loss (3). As a result, the development of anemia could be arrested with parasitological cure, but improvements in blood counts required iron supplementation (18). In contrast, in schistosomiasis, anemia was induced both by blood loss and “anemia of chronic disease.” This latter form of anemia was caused by significant granulosis inflammation induced by parasite eggs trapped in host tissues. In this case, iron stores in the body are sequestered rather than lost, and thus can be mobilized after parasitological cure (9, 16). As a result, successful treatment of schistosomiasis not only resulted in stopping decreasing hemoglobin levels, but in population-based studies, actually increased hemoglobin levels without iron supplementation in the infected population (8–9).

DEWORMING AS A STRATEGY FOR IMPROVING THE HEALTH OF SCHOOL-AGED CHILDREN

With increasing recognition that schistosomiasis and the soil-transmitted helminths had a detrimental impact on a much larger percentage of the infected population and that women and growing children suffered disproportionally from these morbid sequelae, interest in these helminth infections by health officials grew (6). It was also recognized that growing children had long-term detrimental effects of chronic parasitism that could be reversed if regularly “dewormed” (19). The international health communities, specifically the World Health Organization (WHO), began to look into the feasibility of deworming populations on a scale similar to childhood immunizations and distribution of oral rehydration fluid (20–22).

The first obstacle in this effort was to decrease the price of the drugs to make mass treatment financially feasible. Through the efforts of many, including large-scale donations from the pharmaceutical industry, the price of deworming an individual decreased during the 1990s from several dollars per person to just over 10 cents per person.

Because the evolving plan was to use a combination of anti-helminthic drugs to treat several parasitic infections, at the same time it was important to determine the most cost-effective way to deliver treatment, particularly to school-aged children. Such an approach also had to be both safe and effective. The WHO commissioned a double-blind placebo-controlled trial in four locations (two in Africa, two in Asia) using the identical protocol to make this determination (7, 9). This study showed that the two most important drugs, albendazole and praziquantel, could be administered together and that the side effect profile was so low that they could be administered by school teachers and lay community health workers. This study and several additional ones were used to show that mass deworming could have a positive impact on growth stunting, anemia, and cognitive performance. As a result, the concept of deworming a significant percentage of the at-risk children of the world was brought to the international agenda in early 2000 (20–21).

CONCERN OVER DRUG RESISTANCE

Because large-scale chemotherapy-based interventions in malaria failed in the 1950s due to the emergence of drug resistance, concern was raised early on over this issue (23–25). Veterinary studies had shown that too-frequent treatment of worm infections or sub-curative doses of drugs in swine would induce the development of drug-resistant worm strains (26). Thus, the dose and interval between deworming efforts was examined closely. In Egypt there had been communities receiving annual treatment with praziquantel for many years. These communities were examined closely for the emergence of resistance (27). The general conclusion was that, although the risk of inducing drug-resistance was a concern, deworming populations once, twice, and even three times a year did not appear to induce a significant amount of drug resistance (24). In addition, drug-resistant schistosomiasis cases that did emerge under selective pressure were not of clinical or public health significance (28). Based on this work, the WHO began to advocate for implementation of deworming programs throughout the developing world (22).

OPERATIONAL OBSTACLES

Although albendazole is given as a single 400-mg tablet to all children, praziquantel is dosed by weight. This simple fact created an important operational and financial impediment to the implementation of deworming programs in the poorest countries. The cost of a scale for some communities became a financially limiting obstacle. Scales are expensive, they can be lost or broken, and they have commercial uses that could lead to their theft. An ingenious and low-cost solution was thus developed (29).

Dosing of praziquantel was restudied based on height rather than weight and validated in the African pediatric population (30). As a result, a very inexpensive cardboard strip could be attached to a stick or the side of a door and drug dosages easily determined, thus the “dose pole” rather than a scale.

IMPLEMENTATION OF DEWORMING PROGRESS IN AFRICA

Armed with the dose pole, low-cost drugs, and implementation plans developed by both the ministries of education and health in several African countries, the Bill and Melinda Gates Foundation began in 2002 to implement deworming programs in sub-Saharan Africa (31). Organized by the Imperial College in London, successful intervention programs were developed in several African countries which ultimately delivered more than 44 million treatments by 2008 (32).

These population-based interventions were studied closely for their impact on children (32). Periodic application of these drugs resulted in marked decreases in the prevalence and particularly the intensity of parasitic infection. More importantly, at 3-year follow-up, the prevalence of anemia was reduced to almost half and the children's hemoglobin levels increased by more than 1 gram per deciliter over 4 years (33). This work during the first decade of the millennium proved that it was logistically and economically feasible to deworm large numbers of at-risk persons, especially growing school-aged children, and that such periodic treatment would have a positive impact on their health. In addition, such an intervention would compare favorably with other international health interventions such as universal childhood immunizations and insecticide-impregnated bed nets for malaria.

STILL MORE MUST BE DONE

As promising as these interventions were, by 2012 only approximately one third of the at-risk children of the world were being reached by deworming for either schistosomiasis or soil-transmitted helminths (34). The worldwide recession had drained resources for all international aid programs. The effort needed more partners, needed an even better plan, and needed an even greater “bang for the buck.” There is opportunity for expanding these deworming efforts, largely directed at the soil-transmitted helminths. Addressing schistosomiasis requires considering a larger group of diseases that need periodic chemotherapy-based interventions. These efforts will address illnesses that are referred to as “neglected tropical diseases.”

Such a combined effort makes sense. Different diseases have different geographic distributions and micro-ecologies, but they all share the logistic problems of drug procurement, distribution, and delivery. In some cases, the same drug is used against different diseases. With lymphatic filariasis, for example, albendazole is used, and this drug is also effective against hookworms and ascariasis. Thus, if annual filariasis interventions were timed properly with schistosomiasis and soil-transmitted helminth treatments, you could deworm a population twice a year.

Using this integrated approach, it is hoped that the battle against 13 “neglected tropical diseases” will join the current priorities of HIV/AIDS, TB, and malaria on the international health agenda.

CONCLUSION

Helminths or worm infections are among the most common infections of mankind. They principally affect poor people in poor countries and thus have received less interest scientifically and significantly less resources worldwide. Despite the large number of infected humans, most worm-induced pathology is often masked by important cofactors, such as malnutrition, micronutrient deficiency, poverty, and co-infections with other pathogens. Through the careful longitudinal study of worm infections over time and the careful study of populations following curative chemotherapy, we now know that periodic deworming is highly beneficial and now cost effective. It is hoped that worldwide deworming programs will join the international efforts to improve the health of our planet during the next decade.

DISCUSSION

Schiffman, Providence: Beautiful presentation. Dick, how many times do you have to deworm these kids? It can't be just once.

Olds, Riverside: No. In fact, that was part of the take-home message: that you have to keep them free of infections. Now the periodicity depends on the species. So, hookworms and schistosomes can be very effectively dewormed on an annual basis. The hardest to treat is ascaris. Ascaris requires treatment at least three times a year, and an integrated strategy could help. Albendazole is used to treat lymphatic filariasis periodically as part of its annual intervention. If you can alternate filariasis treatment with schistosome and soil-transmitted helminths interventions, you could end up giving albendazole (effective against ascaris) twice a year. So, the periodicity of chemotherapy-based treatments depends on which diseases are endemic in the country, and there is a way through a combination of integrated efforts to get more bang for our buck and end up with treatment two to three times a year for ascaris.

Dale, Seattle: It really was an interesting talk. Thanks. I just wondered if you would say a word about prevention or I would say “shoes, screens, and sewers.”

Olds, Riverside: Well ultimately, you know, the solution to these problems is basically the solution that the Japanese had. Japan was a highly endemic area for schistosomiasis (in their two southern perfectorates) and, of course, they solved the problem by basically having flush toilets everywhere in the country and basically proper sanitation. Shoes, et cetera, obviously can have a major impact on the soil-transmitted helminthes, and fecal-oral contamination can be eliminated or reduced by proper hygienic handling of food. The problem is that this degree of economic development is probably decades away in many areas of the world. So, those of us that like to refer ourselves as kind of the “light a candle” people, we try to do something positive now before we can actually change the social circumstances of everyone in the world. So, these interventions, although they do not solve the ultimate public health problems necessary to eradicate this disease, can have a very positive economic and health impact today. Deworming, in a sense, is what we do with our dogs and cats today. As you may know, we give deworming medicine to our pets on a regular basis because we know they are healthier as a result. It's cheaper than checking if they have worms and very effective. We are basically advocating that the children in the world deserve the same benefit.

Hochberg, Baltimore: Two questions, one social, sort of, and one medical, with the social one first. So are you anticipating or have you seen difficulties with administering this program based on political considerations as has been seen with vaccination programs, and then the medical question is, you referred to the fact that you will reduce TH2, change the TH2 to the TH1. A long time ago, Greenwood speculated that before we knew about TH1 and TH2 that parasitic diseases were protecting native Africans against some inflammatory autoimmune diseases and now we have the so-called hygiene hypothesis. So, if this is successful, do you then anticipate an emergence of Western diseases among the children in the areas that will be treated?

Olds, Riverside: Well the answer to the first question is obvious. For instance, guinea worm should have by now been eradicated from this planet. It probably should have been the very next eradicable disease and it's not been eradicated because it continues to be endemic in the areas of armed-conflict of South Asia and Africa. So, clearly political instability is a major barrier for the implementation of any healthcare problem. There is no doubt about that. The second issue is more speculative. Basically, the yin and yang of the immune system creates interesting possibilities. I am certainly aware of that particular hygienic hypothesis. I think the good news here is that in our attempt to not have the emergence of drug resistance, the interval between treatments is sufficiently long so that basically there is still a small degree of transmission that will take place. For this reason African children will never truly be worm free. We know from animal husbandry practices that if we deworm on a very frequent basis, such as in the case of swine husbandry, where it can be every 2 weeks, you drive the development of drug resistance. So, we are not advocating any more than three-times-a-year treatment. The advantage of that approach is that the children will not be completely free of worm infections for long periods. On the other hand, the statistics around tetanus titers following immunization are quite impressive. If you follow-up deworming with childhood immunizations 2 to 3 months later, you get a better immune response to the vaccine. So, I think given on balance, we are far better off deworming and immunizing than being worried about the potential negative impact of keeping children free from all worm infections. I assume, in my lifetime that will never be achieved.

Greenberg, Houston: There is an increased interest in vaccine development for many of these tropical diseases such as hookworm. Where do you feel that fits in in the next few years in terms of pharmacology versus immunization?

Olds, Riverside: Well, clearly this is a short-term plan. Not only do we ultimately hope that there are vaccines, I have worked on a schistosomes vaccine most of my professional career. There is currently a hookworm vaccine under development, but the implementation of those vaccines has turned out to be quite challenging. I think of greater concern is the small number of anti-parasitic drugs that we have. We only have the drugs we have today because the veterinary science has come up with them. So, whenever you have a limited number of drugs in a chemotherapy-based intervention, you have the risk, as we experienced in malaria, of drug resistance ultimately checkmating this type of approach. Again, I think deworming with drugs is one of those short-term interventions. We will need to deworm children, in my opinion, on a periodic basis until we have a better strategy and that better strategy would clearly be either improvement in social hygiene, nutrition et cetera, or the development of effective vaccines or development of alternative drugs. In the meantime, we have cheap drugs available that we know will have a positive impact on children, and I think we have to organize to get them implemented in the world.