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Institute of Medicine (US) Forum on Microbial Threats. The Causes and Impacts of Neglected Tropical and Zoonotic Diseases: Opportunities for Integrated Intervention Strategies. Washington (DC): National Academies Press (US); 2011.

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The Causes and Impacts of Neglected Tropical and Zoonotic Diseases: Opportunities for Integrated Intervention Strategies.

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A4THE NEGLECTED TROPICAL DISEASES: CURRENT STATUS OF CONTROL AND THE U.K. CONTRIBUTION

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Imperial College, London

Introduction

The neglected tropical diseases (NTDs) are an ever-growing list of infections that predominate in the tropics and are neglected in comparison with the “big three”: malaria, tuberculosis (TB), and HIV/AIDS (Hotez et al., 2008). The current list includes parasitic helminths, bacteria, protozoa, fungi, ectoparasites, and viruses. One subgroup of the NTDs is the group of seven, which are deemed “tool ready” insofar as they can be treated with safe and effective drugs that must be taken usually just once a year, although frequency may be determined by prevalence and intensity or whether the target of the treatment strategy is control or elimination (Hotez et al., 2006b). Because of drug donations by the pharmaceutical industry, these seven are usually targeted using mass drug administration (MDA). The target group may be the whole population of a given area or it may be confined to school-age children, again depending on the prevalence and intensity and the aim of the intervention. One or two of the NTDs may soon be eradicated if final efforts are successful. Some of the NTDs are extremely pathogenic, and so new drugs against them are being sought, usually with donor funding. These diseases do not lend themselves to MDA; rather diagnosis and treatment is the strategy. The rest of the NTDs are probably best described as the “even more neglected tropical diseases” because they are either less pathogenic or less frequently encountered. The exception is dengue fever, which is neglected despite an apparent increase in distribution and prevalence. Many of the NTDs will eventually disappear as they have in the developed world when socioeconomic status improves and clean and safe water and sanitation is available to all. Currently, with 1 billion individuals—one-sixth of the human population—living in poverty and often in extremely unhygienic conditions, such development is some way off.

The Seven Tool-Ready NTDs

The seven include six helminths, lymphatic filariasis (LF; elephantiasis), onchocerciasis (river blindness), schistosomiasis (bilharzia), and soil-transmitted helminths (STHs), of which there are three (ascariasis, trichuriasis, and hookworm), and trachoma, which is caused by the bacteria Chlamydia.

The Pathology and Need for an MDA Control Strategy (Ottesen, 2006)

Lymphatic filariasis (LF) is caused by two similar species of filariasis worms, Brugia malayi and Wuchereria bancrofti. They are each transmitted by mosquitoes, and the adult worms inhabit the lymph glands, which they block and therefore restrict lymph drainage. The gross consequence of LF is first a swelling of limbs, and the grosser deformities that occur are usually the result of secondary infections. In females, the breasts and legs are where the swellings typically appear and the extent can be grotesque. In men, legs and the scrotum can be affected, in which case the resulting hydrocele in males may also result in massive scrotal swellings. The definitive numbers of people suffering from these deformities is not known, but an estimate of 40 million is often quoted. The adult worms live for up to 6 years, and the female worms give birth to larvae (microfilariae), which travel around the skin of the human host waiting to be taken up during a mosquito blood meal. Transmission takes place when another human is bitten by an infected and infective mosquito. It has been discovered that an annual dose of either albendazole with Mectizan (ivermectin) or albendazole with diethylcarbamazine (DEC) will not kill the adult worms but will prevent any larvae from circulating in the skin. The theory, therefore, is that if sufficient people in an endemic area can be treated with these combinations of drugs, no larvae will be available for the biting mosquitoes, and so transmission could be interrupted. If this could be achieved for seven consecutive years—longer than any adult worms will survive in their human host—then elimination of LF might be possible. The distribution of LF globally is widespread, and the Indian subcontinent, the Far East, Africa, and South America are all endemic for LF. The control using MDA is under the umbrella of the Global Alliance for the Elimination of LF (GAELF); however, full control will need significant case management for sufferers with symptoms. Currently, after an exponential increase in coverage from 1998, more than 550 million doses of albendazole are distributed annually—some 80 million with Mectizan and the rest with DEC. The albendazole has all been donated by GlaxoSmithKline (GSK), and more than 2 billion tablets have already been distributed since the start of the programme. Some of the earlier programs have already completed their planned intervention, and transmission has halted in Egypt and Zanzibar. As for case management, washing of swollen limbs regularly with soap has been shown to be very beneficial, and surgery for enlarged scrotal sacs is becoming more available to men with hydroceles.

Funding for GAELF comes from various sources, including the Bill & Melinda Gates Foundation and the British Government Department for International Development (DFID). Other funding for delivery of the donated drugs comes from the U.S. Agency for International Development (USAID), via a contractor and grantees, and a network of nongovernmental organisations (NGOs) also contribute funding and assist with organization of albendazole and Mectizan delivery. The Liverpool School of Tropical Medicine housed the Global Alliance secretariat and now the Centre for Neglected Tropical Diseases, which now works closely with the Schistosomiasis Control Initiative (SCI; see below).

Onchocerciasis (river blindness) is caused by the filarial worm Onchocerca volvulus. Onchocerca volvulus is transmitted by black fly (Simulium species), and the adult worms inhabit nodules in various parts of the body. The adult worms are long lived and, like LF, the female worms give birth to larvae (microfilariae) that travel around the skin of the human host, waiting to be taken up during a Simulium blood meal. Tr ansmission takes place when another human is subsequently bitten by an infective fly. Unfortunately, the many microfilariae cause intense itching in their human host and also cause blindness as the traveling microfilariae damage the retina. The very high infection and blindness rates in villages in close proximity to African rivers in which the Simulium breed led to an intensive vector control campaign in the middle of the 20th century, when many rivers in 11 countries were sprayed with DDT to control the black fy populations. (The Onchocerciasis Control Project [OCP] was launched in 1974.) In the 1980s it was discovered that an annual dose of Mectizan (ivermectin), although it does not kill the adult worms, prevents any larvae from circulating in the skin. Because the larvae do the damage, an annual dose of Mectizan in an endemic area targeting the whole population should prevent blindness. Indeed since 1985 many millions of people have been treated annually in a campaign of preventive chemotherapy, and, although this campaign is still needed, the prevalence rates and blindness rates have been very significantly reduced. The distribution of onchocerciasis is mainly in Africa, although there are foci in South America. The OCP was closed in 2002, by which time an estimated 600,000 had been saved from blindness. The OCP was replaced by the African Programme for Onchocerciasis Control (APOC), which now targets 19 different countries, concentrating on getting annual Mectizan treatment out to those who live in hypoendemic areas. The Mectizan is provided to the countries who qualify by the Mectizan Donation Programme, which is housed within the Task Force for Global Health in Atlanta. The key to APOC is community-directed treatment with ivermectin (Boatin, 2008; Boatin and Richards, 2006). The donated ivermectin is distributed by trained community volunteers who deliver the ivermectin annually to the community using a dose pole to get the correct dose.

In some areas a new strategy of delivering two treatments of Mectizan per year has been instigated with a view to trying to kill the adult worms rather than merely reducing the microfilaria levels.

Funding for APOC comes from a number of traditional bilateral donors, including DFID, and in fact DFID recently (2009) donated an additional £5 million to APOC. Other funding for delivery of the donated drugs goes to the countries from USAID, via RTI,4 and a network of NGOs also contributes funding and assists with organization of Mectizan delivery.

Loa loa is another filarial worm with a limited geographical distribution and relative harmless symptoms, whose major significance is the complication it brings to the MDA against onchocerciasis and LF in Africa. Individuals with a heavy Loa loa infection may suffer serious side effects when treated with Mectizan and albendazole because of death of Loa loa microfilariae.

Schistosomiasis (bilharzia) is caused by species of the genus Schistosoma. S. mansoni causes intestinal schistosomiasis and is found in Africa and the Middle East and has been exported to South America and the Caribbean; S. haematobium causes urinary schistosomiasis—recently renamed urogenital schistosomiasis— and is limited to Africa and the Middle East; S. japonicum and S. mekongi cause intestinal schistosomiasis in the Far East, and S. intercalatum causes schistosomiasis in small foci in central Africa. In all it has been estimated that more than 200 million people may have been infected with schistosomiasis both in 1970 and in 2002 although, because of treatment, other control efforts, population increases, and water resource developments, the distribution of the various species may have changed (Steinmann et al., 2006). The adult schistosome worms are each about one centimetre in length and live in pairs in the blood vessels of the human host; each female worm will lay an estimated 300 eggs per day over a life span of 5–6 years for S. haematobium to up to a reported 20 years for S. mansoni. The eggs break through the blood vessels into either the bladder or the intestine, causing detectable blood in the urine and less so in the stool. The eggs that do not leave the body via the excreta cause significant damage; S. mansoni eggs collect in the liver, where they are trapped, and when they die they cause fibrosis over a period of time, which is shorter in heavier infections. S. haematobium eggs cause lesions in the genital areas and also cause fibrosis of the bladder wall. In Egypt, where S. haematobium used to be particularly prevalent, bladder cancer was the most prevalent cancer in the country until the year 2000. A concentrated treatment programme throughout the 1990s and a change in water usage after the construction of the Aswan High Dam led to S. haematobium being all but eliminated from Egypt, and the associated bladder cancer rates have declined dramatically (Fenwick, 2000, 2006). Five large-scale control programmes were carried out during the period 1970–2000. The first was the Blue Nile Health Project in Sudan, which combined malaria control using indoor residual spraying with praziquantel treatment and mollusiciding. Meanwhile, Brazil embarked on a control programme using treatment of identified cases with first oxamniquin and then praziquantel to reduce the cases of massive liver damage. The others, slightly later, were World Bank–funded programmes in China, the Philippines, and Egypt. The current preferred drug against schistosomiasis is praziquantel, which is available as 600 mg tablets, and a dose of 40 mg/kg is considered curative. Merck donates 20 million tablets a year to the World Health Organization (WHO), and it distributes these to countries looking to initiate programmes. Control of schistosomiasis was initially focused on snail control from 1910 to 1950 because the various treatments for schistosomiasis were unpleasant and relatively ineffective. A few promising agents were tried from 1950 through 1980, but each of them proved to have significant side effects. In 1980, the drug praziquantel was marketed by Bayer after multicentre drug trials were successful, but the price of $1 per tablet was prohibitive. By 1990 a competitive process for manufacture by Shin Poong, a company in South Korea, led to a precipitous reduction in price, and by 2002 the tablets were available at 7 cents per tablet—a 93 percent reduction from the original price (Fenwick, 2008). Despite this reduction, African governments did not rush to buy because the demand for treatment was not high, and yet the numbers requiring treatment represented a very high percentage of the rural population. The leadership for control since 2000 has come from SCI, based at Imperial College London, and was established with a grant awarded by the Bill & Melinda Gates Foundation. Control programmes were established in six countries (Burkina Faso, Mali, Niger, Tanzania, Uganda, and Zambia), and the intention was to lead to national coverage. Programmes focused on MDA to school-age children and in areas of prevalence more than 50 percent of children and then whole populations were targeted. Fishermen and farmers using irrigation were especially targeted. SCI combined the treatment for schistosomiasis with a single pill of albendazole because the prevalence of STHs among people infected with schistosomiasis was invariably high. By 2008, SCI had delivered more than 40 million treatments to about 20 million people, but this still represented only about 10 percent of the infected population in Africa, so expansion of this programme was essential (Fenwick et al., 2009). Additional support came from three sources. The first was a private equity company (Legatum) that funded SCI to organize implementation in Burundi and Rwanda, and this programme has completed three years of treatment of schistosomiasis and STH. The second was USAID, which through RTI has purchased praziquantel for donation to a number of endemic countries as part of its support for NTD control. The third is DFID, which has allocated £25 million for schistosomiasis and STH, £9.5 million for implementation and management, and £15 million to purchase the drugs. SCI and Liverpool Centre for Neglected Tropical Diseases work together on this award.

The current status of schistosomiasis control is that programmes are going ahead in a number of African countries funded by bilateral donations from USAID and DFID. However, WHO believes that less than 10 percent of the people in need of treatment in Africa were treated in 2009, which means that many areas are in need of treatment (Hotez and Fenwick, 2009).

A constraint is the funding to purchase praziquantel, but even if the funding was available there is a doubt whether production capacity is available beyond 150 million tablets a year. However, another constraint is the lack of capacity of many countries to deliver praziquantel widely, and so scaling up might well be slower than ideal even if funding was made available. Nevertheless, in many countries now the most serious cases of hepatosplenomegaly seem to be on the decrease. One aspect of schistosomiasis that was recently brought to the attention of the medical community is the association between S. haematobium and HIV/ AIDS, which is why the term urogenital schistosomiasis was recently adopted (Kjetland et al., 2010a, 2010b).

We firmly believe that a stronger case needs to be made for the treatment of young children ages 6–14 with an extra focus on ensuring that young girls, whether in or out of school, are reached with schistosomiasis treatment before genital lesions are developed and therefore the chances of HIV/AIDS are significantly reduced (Hotez et al., 2009).

Soil-transmitted helminths (Ascaris lumbricoides, Trichuris trichuris, Necator americanus, and the less common Ancylostoma duodenale) The four species of STH, which actually are three diseases—roundworm, whipworm, and hookworm—infect different parts of the digestive tract and have different modes of infection, although none of them use an intermediate host.

Roundworms It is estimated that more than 800 million individuals are infected with roundworm and that most of these are children. It is also likely that most people are not heavily infected and that 10 percent of those infected harbor 90 percent of the worms. However, 10 percent of 800 million means that 80 million people have dangerously heavy worm loads. Roundworms live in the small intestine, and their eggs are passed out in the feces. The eggs need to spend time developing in the soil in not-too-hot and not-too-dry conditions, and then they are ready to be ingested. If ingested, the eggs hatch and then migrate through the body until they are coughed up and swallowed. They then pass through to the small intestine where they remain, laying eggs and feeding. In heavy infections, the worms, which are thick and up to 14 inches (35 cm) in length, can cause a serious intestinal blockage.

Whipworms An estimated 600 million people are infected with Trichuris worms, which are generally thought to be the least pathogenic of the STHs. They are relatively small (less than 5 cm or 2 inches) and live in the colon. Heavy infections can cause colitis.

Hookworm The two species of hookworm infect almost 600 million people, and their effect on the human host is much greater than the other two types of STH, despite them being the smallest of the STHs at just 1 cm in length. This is because the hookworms attach to the wall of the small intestine and in fact take blood, causing anaemia, which can be severe in heavy infections. Anaemia is the main cause of poor birth outcomes and so hookworms are responsible for a significant number of underweight babies and for anaemia in children and women of childbearing age (Christian et al., 2004). The eggs of the hookworm are passed out in the faeces and then develop in the egg before hatching, releasing a free-living larva. This larva attaches to bare feet or legs and burrows through the skin to reach the bloodstream. Via the heart, they reach the lungs, migrate up the trachea, and are then swallowed.

All three worms are global in distribution, although, thanks to improved sanitation, areas that 100 years ago were heavily infected with hookworm (the classic example being the southern United States) no longer have any hookworm at all.

The worms can be swept from the human digestive system by treatment with a benzimidazole, either albendazole or mebendazole. Neither drug is 100 percent effective, but even if an individual is not completely cleared of worms a high percentage will be swept through the system (Albonico et al., 2004).

Until very recently, the deworming drugs had to be purchased, and, although they were inexpensive (less than 10 cents per dose), few countries organize deworming programmes. From 2008, Johnson and Johnson began a donation program and up to 50 million mebendazole tablets were donated annually to selected countries. From 2010, Johnson and Johnson has reported that it will increase its donation to 200 million tablets a year. Meanwhile, the 2 billion tablets of albendazole that have been donated by GSK for treatment of LF have dewormed millions of individuals annually. In October 2010, GSK announced an increase in its albendazole tablets by 400 million every year to ensure that all school-age children in Africa will be dewormed (Lorenzo Savioli, WHO, personal communication). Another donor has been “Feed the Children,” a programme that has donated many millions of mebendazole tablets for schoolchildren. It can surely be expected that within 5 years children in Africa and the developing world will show improvements in appetite, physical fitness, growth, hemoglobin, school attendance, and cognitive ability (Jukes et al., 2002; Miguel and Kremer, 2004; Nokes et al., 1992). It may be difficult to demonstrate these improvements because of confounding factors, but most parasitologists are convinced of the accuracy of this hypothesis.

Since the millennium, several organizations have increased their deworming activities. SCI has combined deworming with treatment of schistosomiasis. “Children without worms” has handled the Johnson and Johnson donation of mebendazole, “Deworm the World” has accepted Feed the Children mebendazole, and now GSK will donate 400 million tablets per year for Africa, probably through a WHO mechanism. Many NGOs have deworming programs, USAID has included deworming in the integrated NTD treatment programmes, and the United Nations Children's Fund has funded many countries to deworm preschool-age children. In several progressive Asian countries, deworming has been adopted and funded by the state. However, despite all this recent activity, WHO still believes that only 10 percent of people are being dewormed annually.

Trachoma caused by the bacterium Chlamydia trachomitis Known as the leading cause of preventable blindess, Chlamydia is reported to infect some 80 million people worldwide, and up to 8 million may be visually impaired as a result of their infection. As with all the above, this is an infection in the poorest of the poor, and could be easily prevented by improved water and sanitation. Without better hygiene, the infection is carried from person to person both by physical contact and by flies. As with the other diseases, there has been an initiative to control trachoma. The International Trachoma Initiative (ITI) was started by Dr. J. Cook when he left the Edna McConnell Clark Foundation (EMCF), which for many years funded Dr. Cook's tropical disease research. The EMCF provided startup funding, Pfizer joined in with Zithromax donations, and the Bill & Melinda Gates Foundation also supported the programme. In a slightly different approach, ITI insisted on more than just a treatment program and developed a “SAFE” strategy: S, for incorporating simple surgery to correct eyelid deformities and prevent cornea scarring; A, for antibiotics—three annual doses to control active Chlamidia; F, for facial cleanliness to prevent the infection, which leads to conjunctivitis, which will reduce transmission; and finally E, for environmental improvement, including improved water supplies and better sanitation. The first country to eliminate trachoma was Morocco. In 2011 it is estimated that some 70 million doses of Zithromax will be delivered by ITI, which was once independent but is now housed within the Task Force for Global Health.

Integration of Activities Against the Seven Tool-Ready NTDs

WHO, in conjunction with the Global Network for Neglected Tropical Diseases, the Bill & Melinda Gates Foundation, and others, led the drive to bring all the vertical single disease programmes together with a view to integration of the annual MDA programmes. The concept was “sold” to USAID, which resulted in a competitive bid in 2006 for $100 million more than 5 years for integrated MDA, awarded to RTI. This has resulted in 10 countries receiving support for integrated NTD treatments and more than 250 million treatments with the four drugs being delivered.

In 2010, further funding for integrated NTD treatment is on the table again from USAID—and this time up to $450 million may be awarded to several contractors. By November 2010 Family Health International had been awarded $100 million for each of Africa and Asia to take established programmes forward.

Other Neglected Tropical Diseases

Guinea Worm: Dracuncula medinensis

Guinea worm is a nasty worm infection that affects man and water fleas. From more than 3 million infected some 20 years ago, it is estimated that in 2010 only 25,000 cases remain in the world; most of those cases are in South Sudan because of hostilities that have prevented clearance. The latest country to be declared free of Guinea worm was Burkina Faso. The larval worm lives in a water flea and is ingested by anyone drinking unclean, unfiltered water from a pond or lake. The larvae are released in the stomach and over several months make their way to the connective tissue in the leg, where the female becomes gravid with eggs. The female worm produces a blister that burns; when the blister bursts, eggs are released into the water to reinfect the water fleas. The effect on the human host is painful, and secondary infection can be very dangerous. Before control efforts were in place, which depend mostly on health education and providing filters for water, whole villages were likely to be infected. There is no drug to treat this worm, but because there is no animal reservoir the chances are great that it will soon be eradicated. The Carter Center and WHO, with support from the Bill & Melinda Gates Foundation and DFID, have worked tirelessly to reduce the number of infections; with the exceptions of Ghana and Sudan, the target of eradication is getting very close (Hopkins et al., 2005; Ruiz-Tiben and Hopkins, 2006).

The Protozoa: Trypanosomiasis and Leishmaniasis (Croft et al., 2005, 2006)

Sleeping sickness and Chagas disease caused by trypanosomes and visceral leishmaniasis are important diseases that have a high mortality rate, killing over 150,000 per year; they have a poor cure rate even when treated. Cutaneous leishmaniasis does not kill but is disfiguring and also difficult to treat.

Sleeping sickness is transmitted by the bite of the tsetse fly, and once infection has developed to disease, mortality is high. At any one time an estimated 500,000 people may be infected. The drugs available even if cases are diagnosed are old, and there is an urgent need to find new treatments, even though they will never be commercial products. The not-for-profit Drugs for Neglected Diseases initiative (DNDi) based in Geneva is following some promising drug development lines with funding from DFID, the Gates Foundation, and the European Union. Screening for human African trypanosomiasis (HAT) used to be more widespread than it is today because the areas worst affected include current conflict areas in East and Central Africa.

Chagas disease is limited to South America because it is transmitted by a triatoma bug, but still an estimated 9 million are infected and therefore suffer from either an acute stage, which can cause heart failure, or a chronic condition that disturbs the heart, causing palpitations, chest pain, and fainting. Although it is caused by a trypanosome, it is thus very different from HAT. However, this disease should be easily preventable by improving housing conditions or indoor insecticide spraying, which will prevent bedbugs. As with other parasitic infections, it is the poorest people who are infected.

Leishmaniasis affects some 12 million people globally and is transmitted by sandflies. The cutaneous form causes ulcers and can be disfiguring, but the visceral form affects internal organs and is fatal if untreated. However, the treatment often causes side effects and is prohibitively expensive to the poor people who tend to be infected.

The Even More Neglected Tropical Diseases (Hotez et al., 2006a)

Many more diseases occur in the tropics and are even more neglected than those mentioned above. There are helminth infections such as strongyloidiasis, Toxocariasis and larva migrans, and loiasis. There are food-borne trematodes,which are very common in the Far East because of the eating of poorly cooked fish. These include opisthorchis, paragonimus, and chlonorchis. The additional Cestodes that affect humans are taeniasis, cysticercosis, and echinococcosis, which include the zoonotic parasitic worms.

Other protozoa include giardiasis and amoebiasis, while bacterial infections include Bartonellosis, bovine tuberculosis, Buruli ulcer, leptospirosis, relapsing fever, rheumatic fever, treponematoses, and syphilis. Two important fungal infections include mycetoma and paracoccidiomycosis; then there are ectoparasitic infections such as scabies, myiasis, and tungiasis. The viral infections include dengue fever, yellow fever, Japanese encephalitis, rabies, and the hemorrhagic fevers.

Thus, although the tool-ready infections can be controlled or eliminated using preventive chemotherapy, there are many more infections that mostly affect the poorest of the poor that are still very neglected. To achieve the Millenium Development Goals, it will be necessary to tackle not only the tool-ready diseases but also the others mentioned in this paper, because poverty and these diseases are inextricably linked (Gil Gonzalez et al., 2006).

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Footnotes

4

Research Triangle Institute (RTI) is better known by its trade name, RTI International.

Copyright © 2011, National Academy of Sciences.
Bookshelf ID: NBK62509

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